The Project Gutenberg eBook of On the mechanism of the physiological action of the cathartics
    
This ebook is for the use of anyone anywhere in the United States and
most other parts of the world at no cost and with almost no restrictions
whatsoever. You may copy it, give it away or re-use it under the terms
of the Project Gutenberg License included with this ebook or online
at www.gutenberg.org. If you are not located in the United States,
you will have to check the laws of the country where you are located
before using this eBook.

Title: On the mechanism of the physiological action of the cathartics

Author: John Bruce MacCallum

Release date: March 17, 2023 [eBook #70308]

Language: English

Original publication: United States: Univ. Press

Credits: Bryan Ness and the Online Distributed Proofreading Team at https://www.pgdp.net (This file was produced from images generously made available by The Internet Archive/American Libraries.)


*** START OF THE PROJECT GUTENBERG EBOOK ON THE MECHANISM OF THE PHYSIOLOGICAL ACTION OF THE CATHARTICS ***





                 ON THE MECHANISM OF THE PHYSIOLOGICAL
                        ACTION OF THE CATHARTICS

                                   BY
                          JOHN BRUCE MacCALLUM

 Late Assistant Professor of Physiology in the University of California

                                BERKELEY
                          THE UNIVERSITY PRESS
                                  1906




                         JOHN BRUCE MACCALLUM.


The following pamphlet was completed only a few days prior to the death
of the author, which occurred on the sixth of April, nineteen hundred
and six. Through his death Physiology was robbed of one of its most
brilliant young investigators.

John Bruce MacCallum was born in Dunnville, Canada, on the eighth day
of June, eighteen hundred and seventy-six. Through the influence of his
father, Dr. G. H. MacCallum, now Superintendent of the State Asylum
at London, Ontario, his interest in the natural sciences was early
aroused and during his college career at the University of Toronto
as much of his time as possible was devoted to these subjects, but
chiefly to biology. After his graduation in 1896 he entered the Medical
School of Johns Hopkins University. Under the influence of Professor
Mall he undertook during his first medical year an investigation
on the histogenesis of the cells of the heart-muscle, and it was
characteristic of him that he began his work in pathological anatomy
also with an original investigation. During the third year of his
medical course he again prepared several anatomical papers and at the
same time assumed the burden of the proof reading and of preparing
the index of Barker’s book on Neurology. It was during this year,
1898-1899, that the first symptoms of the disease appeared which was
to cut short the life of this talented, indefatigable worker. From
this time on he was constantly handicapped in his work by the struggle
against illness.

After his graduation in medicine in nineteen hundred he returned to
Baltimore as assistant of Professor Mall. In nineteen hundred and
one he went to Leipzig to work in the laboratory of His, but his old
enemy again interrupted his work, this time attacking him in the form
of an affection of the apex of the lungs. He returned home as soon as
sufficiently recovered to bear the journey, and upon the advice of Dr.
Osler he spent the winter in Jamaica. During this period he translated
and edited Szymonowicz’s histology into English.

The condition of his health made it impossible for him to live in the
East and in the autumn of nineteen hundred and two he went to Denver,
“where he rented an office and tried to practice. He abhorred the
life, though, and held in contempt the charlatans with whom he came
in contact. There were patients and he made enough money to pay his
expenses in the few weeks he was there, but the repugnance to that
kind of life was too great, and he abandoned his practice. They had
made him teacher of anatomy in their medical school, in charge of the
department, I believe. The students were difficult to manage--their
ideals being far different from his.[1]” The bright spot in his life in
Denver was his association with Dr. Sewall, the former physiologist.

Having accepted a call to the University of California, I offered Dr.
MacCallum a position as assistant in physiology, and we began our
work here together. During the first and second years his health was
tolerably good, but in nineteen hundred and five he undertook a problem
on immunity which was beyond his physical strength and he began to fail
rapidly. He went East to be treated by Professor Osler, returning to
Berkeley in the fall of the same year, in a much weakened condition,
but if he realized how critical was his condition he betrayed it to
no one. He was cheerful and apparently hopeful. As he was not able
to exert himself in experimental work, I suggested that he put the
results of his experiments done at Berkeley into book form.

The present volume is the result of this work, the last done before
death claimed him. It has been published without alteration. The
preface was probably written two days before his death, which came
suddenly--as he had always wished that it might.

MacCallum belonged to that type of scientists whom we may designate
as discoverers. His results were obtained quickly, were made secure
beyond doubt, and were put into such shape that they could easily be
demonstrated by him. But as is also common in the case of discoverers,
his publications were comparatively brief. This may make it at times
difficult for inexperienced or uncritical workers to repeat his
experiments. I may state, however, that they belong to the regular
class exercises of the medical students in our laboratory. Those who
have once learned how to perform them can always count upon their
succeeding.

In his work as well as in his life he was a calm thinker, the reverse
of a hustler. He conceived his experiments in the spirit of an artist
and the realization of his ideas was the poetry his work put into
his life. He did not work for outside success, nor did he pose as a
benefactor of mankind.

Those who have known him well feel that the death of John Bruce
MacCallum has left a gap which will never again be filled.

                                                           JACQUES LOEB.

                                             BERKELEY, November 7, 1906.


FOOTNOTES:

[1] Quoted from a letter from his brother, Professor W. G. MacCallum,
of Johns Hopkins University, to whom I am under obligation for the data
given in this sketch.




                 PUBLICATIONS BY JOHN BRUCE MACCALLUM.


1. Fresh-water Cladocera.

 University of Toronto Quarterly, May, 1895.

2. On the Histology and Histogenesis of the Heart Muscle Cell.

 Anatomischer Anzeiger, Bd. XIII, 1897.

3. On the Pathology of Fragmentatio Myocardii and Myocarditis Fibrosa.

 Johns Hopkins Hospital Bulletin, No. 89, 1898.

4. On the Histogenesis of the Striated Muscle Fibre and the Growth of
the Human Sartorius Muscle.

 Johns Hopkins Hospital Bulletin, Nos. 90-91, 1898.

5. A Contribution to the Knowledge of the Pathology of Fragmentation
and Segmentation and Fibrosis of the Myocardium.

 Journal of Experimental Medicine, Vol. IV, 1899.

6. Development of the Pig’s Intestine.

 Johns Hopkins Hospital Bulletin, Vol. XII, 1901.

7. Notes on the Wolffian Body of Higher Mammals.

 American Journal of Anatomy, Vol. I, 1902.

8. On the Muscular Architecture and Growth of the Ventricle of the
Heart.

 Johns Hopkins Hospital Reports, Vol. IX, 1900. (Memorial volume to Dr.
 W. H. Welch by his pupils.)

9. Text-book of Histology and Microscopic Anatomy. By L. Szymonowicz.
Translated and edited by J. B. MacCallum. Lea Bros., 1902.

10. On the Mechanism of the Action of Saline Purgatives, and the
Counteraction of their Effect by Calcium. (A preliminary communication.)

 University of California Publications, Physiology, Vol. I, 1903.

11. On the Action of Saline Purgatives in Rabbits and the Counteraction
of their Effect by Calcium. (Second communication.)

 American Journal of Physiology, Vol. X, 1903.

 Also: University of California Publications, Vol. I, 1904.

12. On the Local Application of Solutions of Saline Purgatives to the
Peritoneal Surfaces of the Intestine.

 American Journal of Physiology, Vol. X, 1904.

 Also: University of California Publications, Vol.I, 1904.

13. On the Influence of Calcium and Barium on the Flow of Urine. (A
preliminary communication.)

 _Ibid._, 1904.

14. The Influence of Saline Purgatives on Loops of Intestine Removed
from the Body.

 _Ibid._

15. The Secretion of Sugar into the Intestine Caused by Intravenous
Saline Infusions.

 _Ibid._

16. The Action of Cascara Sagrada. (A preliminary communication.)

 _Ibid._

17. The Influence of Calcium and Barium on the Secretory Activity of
the Kidney. (Second communication.)

 University of California Publications, Physiology, Vol. II, 1904. Also
 in the Journal of Experimental Zoology, Vol. I, 1904.

18. Ueber die Wirkung der Abführmittel und die Hemmung ihrer Wirkung
durch Calciumsalze.

 Pflüger’s Archiv, Bd. 104, 1904.

19. The Action on the Intestine of Solutions Containing two Salts.

 University of California Publications, Vol. II, 1905.

20. The Action of Purgatives in a Crustacean (_Sida Crystallina_).

 _Ibid._, 1905.

21. On the Diuretic Action of Certain Haemolytics, and the Action of
Calcium in Suppressing Haemoglobinuria. (A preliminary communication.)

 _Ibid._, 1905.

22. The Diuretic Action of Certain Haemolytics and the Influence
of Calcium and Magnesium in Suppressing the Haemolysis. (Second
communication.)

 _Ibid._, 1905.

23. The Action of Pilocarpine and Atropin on the Flow of Urine, by John
Bruce MacCallum.

 _Ibid._

24. Factors Influencing Secretion.

 The Journal of Biological Chemistry, Vol. I, 1906.




                           AUTHOR’S PREFACE.


The following pages contain an account of a long series of experiments
made to determine the action of saline purgatives. Many of the results
have been separately published in various scientific journals, and they
are now gathered together with certain new material in an attempt to
give as connected and complete an account as possible of the action of
this class of drugs.

The experiments were begun at the suggestion of Professor Loeb, to
whom I am greatly indebted for the constant interest which he has
taken in the work, and whom it is a pleasure to thank for many helpful
suggestions.




                               CONTENTS.


                                                                    PAGE

  Chapter I.--Normal Movements and Secretion of the Intestine          1

  Chapter II.--The Subcutaneous and Intravenous Injection of
  Saline Purgatives                                                    9

  Chapter III.--The Local Application of Saline Solutions to the
  Peritoneal Surfaces of the Intestine                                23

  Chapter IV.--The Production of Increased Secretion of Fluid
  into the Intestine by the Saline Purgatives                         29

  Chapter V.--The Inhibiting Action of Calcium and Magnesium
  on the Movements and Secretion of the Intestine                     38

  Chapter VI.--The Action of Saline Solutions on Loops of Intestine
  Removed from the Body                                               50

  Chapter VII.--The Action on the Intestine of Solutions Containing
  Two Salts                                                           57

  Chapter VIII.--The Effect on the Intestine of Intravenous Saline
  Infusions                                                           65

  Chapter IX.--Mode of Action of the Saline Cathartics                74

  Chapter X.--Possible Therapeutic Value of These Experiments         83

  Chapter XI.--The Action of Purgatives of Vegetable Origin           86




                              CHAPTER I.

           Normal Movements and Secretion of the Intestine.


A. _Normal Movements of the Intestine._

The normal movements of the intestine have been described by many
observers, and in these descriptions there is a fair amount of
uniformity. Ludwig and his pupils, Bayliss and Starling, Magnus and
others have studied this subject with much care. In such a complicated
organ as the intestine there are many sources of error, and differences
of opinion may readily arise if an attempt is made to analyze too
closely the functions of the various tissues making up the intestine,
to decide for example whether the movements are of nervous origin or
muscular, or whether the secretion is dependent primarily on the blood
supply or on the nervous system. For our purpose it will be sufficient
to regard the intestine as an organ composed of certain muscular
layers, certain nervous plexuses and certain glands--and to discuss the
action of various influences not on these separate tissues, but on the
organ as a whole, holding in mind also the nervous and bloodvascular
connections of the organ.

If the abdominal cavity of a dog, cat, or rabbit be opened under the
surface of m/6 NaCl solution or Ringer’s solution at body temperature,
it will be found that the intestines are not entirely at rest.
According to local conditions, more or less active movements will be
seen. These were described by Ludwig and others as consisting of two
kinds of motion, namely, the _pendulum movements_, and _peristaltic
movements_.

The pendulum movements are rhythmical, and consist of a regular slight
swinging of the loops upon one another. Their frequency has been
measured by Bayliss and Starling.[2] According to these observers, each
contraction and relaxation lasts 5 to 6 seconds, so that the rhythm
consists of 10 to 12 beats per minute. The rhythm is however not always
regular, the contents of the loop and other local conditions exerting
an influence. The cause of these pendulum movements is not perfectly
clear. By many they have been ascribed to a rhythmical shortening of
the intestine, _i.e._, a rhythmical contraction and relaxation of the
longitudinal muscle coat. Mall[3] regards them as arising mainly in the
circular layer; while Bayliss and Starling state that they are due to
simultaneous contractions of the circular and longitudinal coats.

The peristaltic movements consist of more or less strong contractions
of the circular coat of the intestine, varying from a slight ring-like
contraction which passes rapidly down the gut to a violent constriction
of the intestine which obliterates the lumen of the gut and passes
very slowly from above downward. The slight contractions may travel,
according to Bayliss and Starling, as rapidly as 2-5 cm. per second,
while the more violent ones move not more than ¹⁄₁₀ cm. per second.
According to Nothnagel, Mall, and others, the formation of these
peristaltic waves is always due to a local stimulus, usually the
presence of a bolus of food. The intestine contracts immediately above
the point of stimulation and the mass of food is forced downward. The
wave of contraction follows close behind the bolus, while for some
distance above this point similar waves run downward until they reach
the mass of food. The gut is usually relaxed below the bolus, and
the general statement has been made that a stimulation at any point
causes a contraction above that point and an inhibition below it.
It is generally thought that Auerbach’s plexus is concerned in the
propagation of the peristaltic wave since the peristalsis takes place
also when the intestine is separated from the central nervous system,
and does not occur when nicotine or cocaine is given to paralyze the
intrinsic nerves of the intestine.

In addition to the pendulum and the peristaltic movements, there is a
third quite distinct motion to be observed in the intestine. The normal
peristaltic movements are very slow, while this third type, called by
Nothnagel “Rollbewegung,” consists of a rapid contraction which may
pass from one end of the intestine to the other in 1 to 2 minutes. The
function of this movement is thought to be the rapid elimination of
irritating substances from the intestine. It occurs irregularly and is
more common in slight pathological conditions of the gut.

It is generally believed that the normal peristaltic wave passes only
from above downward, and never in the reverse direction. This has been
shown in many ways. Mall[4] removed a certain length of the small
intestine and reversed it so that the end which had originally been
nearer the stomach was now in the position formerly occupied by the
end nearer the rectum. The food would not pass down this part of the
intestine, but accumulated above it. In other words, the peristalsis
continued as it was before the loop was removed, the wave passing in
the reversed loop from below upward. A further illustration of the same
thing is seen in the fact that in an isolated loop an object inserted
in the gastric end of the loop will rapidly be passed to the other
end, while it is impossible to force the object into the rectal end
because of the peristaltic waves which constantly expel it. Grützner[5]
observed that the intestinal contents sometimes move backward and
forward in the intestine, and that an easily recognizable substance,
_e.g._, food introduced into the rectum _in enemata_, was sometimes to
be found afterwards in the stomach. It seems further from Cannon’s[6]
study of the cat’s intestine by means of the Röntgen rays that
antiperistalsis certainly takes place in the colon of this animal. In
the transverse and ascending colon antiperistaltic waves occur at the
rate of 5-6 per minute. No antiperistalsis was observed in the small
intestine.

_Factors which normally cause or influence the intestinal movements._
Although there has been some divergence of opinion on the subject, it
is now generally held that anaemia of the intestine causes a cessation
of all movements. This has been shown by van Braam-Houckgeest,[7]
Mall,[8] and others. Clamping of the aorta, opening of the heart, etc.,
cause all movements to cease. Hyperaemia of the intestine on the other
hand causes active movements to arise. Any conditions which cause a
venous engorgement of the intestine bring about intestinal movements.
Bokai[9] found that CO_{2}, is a direct stimulant to the intestine, and
that the movements may be stopped by the application of oxygen. Krause
and Heidenhain first noticed that when an animal’s breathing is stopped
the peristaltic movements of the intestine greatly increase, but cease
when the breathing is recommenced.

The influence of the intestinal contents upon the movements of the
gut was discussed as long ago as 1750 by Foelix.[10] Among the later
authors to treat of this subject is Bokai. In addition to indigestible
and irritating substances taken in with the food, there are certain
substances ordinarily formed in the intestine by decomposition which
cause peristaltic movements. Among these are CO_{2}, CH_{4}, and
H_{2}S. All of these gases which are more or less constantly formed
help in keeping up the normal movements of the intestine. Certain
faecal constituents have also the same effect. Bokai mentions among
these a number of organic acids--lactic, succinic, butyric, formic,
propionic, acetic, caproic, and caprylic acids. There is no doubt also
that the salts taken in with the food exert a considerable influence.

The intestine is to some extent also under the influence of extrinsic
nerves. As shown by Pflüger,[11] the splanchnic nerves exert an
inhibitory action on the intestine, so that their section causes
intestinal movements and their stimulation brings about a cessation
of peristalsis. This has been ascribed by some authors to the
vasomotor action of the nerves. Concerning the action of the vagus
there has been difference of results. Many experimenters have found
that stimulation of this nerve causes contractions of the intestine.
Others have obtained no results. If, however, the splanchnics be cut
and the inhibitory impulses abolished, stimulation of the vagus gives
constant results consisting of a slight inhibitory action followed by
an increase of the rhythmical contractions of the intestine.


B. _Normal Secretion Into the Intestine._

It is probable that under normal conditions a fluid is secreted from
the entire length of the intestine, but this fluid undoubtedly differs
somewhat in the various parts. The duodenum with Brunner’s glands, the
jejunum and ileum with the glands of Lieberkühn and the large intestine
in which there is a preponderance of mucus cells may be assumed to
give secretions which are not identical. The methods which have been
used to obtain the succus entericus for analysis are subject to
criticism, and much remains to be discovered with regard both to the
mechanism of secretion and the nature of the normally secreted fluid.
The most fruitful method has been that instituted by Thiry,[12] and
later modified by Vella.[13] This consists of the establishment of a
permanent fistula from the intestine through the skin from which the
intestinal juice may be gathered after complete healing has taken
place. This is commonly known as a Thiry-Vella fistula. In general
it has been observed that practically no fluid is secreted into the
intestine without a stimulus of some sort. Electrical or mechanical
stimulation as well as the introduction of food causes a yellowish
fluid to pour into the gut. Pregl[14] has studied the secretion by
this method in a lamb. Here he finds a continuous secretion which
is increased after the taking in of food. It possesses a distinctly
alkaline reaction, and contains carbonates, chlorides, and a
considerable quantity of proteid. It also contains urea. For a complete
analysis the reader is referred to Pregl’s article. The intestinal
juice of the lamb has no digestive action on proteids. There was formed
from starch paste a fermentable sugar. Cane sugar and maltose were
inverted, but milk sugar remained unchanged.

The influence of the nervous system on the secretion of intestinal
fluid is very clear. It was found by Moreau[15] that section of the
nerves to the intestine brought about a large secretion of fluid
into the intestine resembling closely that obtained by a Thiry-Vella
fistula. Budge[16] had previously noted that extirpation of the ganglia
of the coeliac plexus caused an increase of fluid in the intestine.
The results of Moreau, who carried out his experiments with isolated
loops, have been repeatedly confirmed, and some question has arisen
as to the nature of the fluid secreted, some authors regarding it as
a transudation, others as a true secretion. It has been compared by
some to the rice water stools of Asiatic cholera, and on account of the
analogy with the secretion which pours from the salivary gland after
section of the chorda tympani it has been called a paralytic secretion.
Landois[17] ascribes the secretion to the cutting of vasomotor nerves
which causes circulatory changes so marked that a transudation of
fluid occurs. In the leg, however, it has been shown that the normal
transudation and lymph formation are not increased by section of the
nerves. One would also expect to find oedema of the intestinal wall
if this were a process of transudation due to vascular changes. Such
oedema does not occur.

The nature of the fluid obtained by section of the nerves to the
intestine has been studied by many investigators. Moreau described it
as a light yellow clear fluid with a strongly alkaline reaction. Its
specific gravity is 1.008. It contains carbonates, chlorides, organic
materials and a little urea. According to Hanau,[18] the fluid contains
no digestive ferments, although in the dog he found that in the first
part of the secretion fibrin was digested to some extent and starch
converted into sugar. This he ascribed to the presence of pancreatic
juice. Mendel[19] has recently worked on this subject and finds also
that the pure paralytic secretion has no digestive action on fibrin,
but that there is a slight amylolytic action. Cane sugar and maltose
are inverted, while milk sugar is not.

The fact that the paralytic secretion resembles very closely the normal
secretion both physically and chemically seems to indicate that it is a
true secretion and not a transudation.

Bottazzi[20] has recently found that an extract of the small intestine
injected into the blood causes not only an increase in the fluid
secreted into the intestine, but also an increase in the peristaltic
movements. This extract is an aqueous one, the nucleoproteids being
precipitated by acetic acid. It thus contains the secretin of Bayliss
and Starling and is capable of increasing also the pancreatic
secretion. The fluid produced in the intestine was later analyzed
by Bottazzi and Gabrieli[21] and proved to be quite similar to the
normal intestinal secretion. It is of some interest to note that the
intestinal secretion and the pancreatic secretion are simultaneously
augmented by the intravenous injection of this extract.


FOOTNOTES:

[2] Journal of Physiology, Vol. XXIV, 1899, p. 99.

[3] Johns Hopkins Hospital Reports, Vol. I, 1896.

[4] _Loc. cit._

[5] Deutsch. Med. Wochenschr., XV, 1899.

[6] Amer. Journ. Physiol., Vol. VI, 1902.

[7] Pflüger’s Archiv, VI, 1872; VIII, 1874.

[8] Johns Hopkins Hospital Reports, I, 1896.

[9] Arch. f. exp. Path. u. Pharm., Bd. 23-24.

[10] De Motu peristaltic. intest. Treviris, 1750.

[11] Über das Hemmungsnervensystem f. d. peristal. Bewegungen d.
Darmes, Berlin, 1857.

[12] Sitzungsb. d. k. Akad. d. Wissensch. Wien, 1864, Bd. 1.

[13] Untersuchung. z. Naturl. d. Mensch. u. d. Thiere; 1881; Bd. XIII.

[14] Arch. f. d. gesammte Physiologie, Bd. LXI, 1895, S. 359.

[15] Centralbl. d. Medicin. Wissensch., S. 209, 1868.

[16] Verhandl. d. K. K. Leop. Carol. Akad. d. N., Bd. 19, 1860.

[17] Lehrbuch der Physiologie, 10th Ed., p. 360.

[18] Zeitsch. f. Biologie, Bd. 22, 1886, p. 195.

[19] Arch. f. d. ges. Physiol., Bd. 63, 1896, p. 425.

[20] Arch. di Fisiologia, 1904, I, 413.

[21] Arch. internationales de Physiologie, 1905, Vol. III, II, p. 156.




                              CHAPTER II.

   The Subcutaneous and Intravenous Injection of Saline Purgatives.


Although it has long been known that many of the vegetable purgatives
act as well when introduced into the circulation as when taken by
mouth, it has generally been stated that saline purgatives are
inactive when injected either subcutaneously or intravenously. It
has even been claimed that they have the opposite effect, causing
constipation. Claude Bernard,[22] however, states that sodium sulphate
causes purgation when introduced into the circulation, although he
gives no experiments to support the assertion. Buchheim[23] believed
that intravenous injection of purgative salts produced no purgation.
Rabuteau[24] stated that the injection of a large amount of sodium
sulphate into the blood caused constipation in a dog, an experiment
which he took to prove that the strong solution outside the intestine
withdrew fluid from the lumen by its endosmotic power. Headland[25]
advanced the view that all medicines act after being absorbed into
the blood, and that saline cathartics are first taken up into the
circulation and stimulate the intestine in being later excreted by
the intestinal glands. Carpenter reported an experiment in which he
obtained a purgative action by introducing magnesium sulphate into the
stomach after this organ had been separated from the intestine by
a ligature. It was further found by Vulpian[26] that small doses of
magnesium sulphate, but not of sodium sulphate, acted as purgatives
when injected subcutaneously. Hay[27] gives an excellent resumé of
the literature on this subject. Although he considers it already
proven that purgatives do not act when injected subcutaneously or
intravenously, he has made a number of experiments to confirm this
idea. He was unable to obtain any purgative effect in dogs and cats by
the introduction into the blood of 10% Na_{2}SO_{4} or 20% MgSO_{4}.
With the subcutaneous injection of these salts, however, a purgative
action was sometimes produced. This he attributed to the local
irritation of the injection. It will be noted that the conditions of
these experiments are by no means ideal. Hay injected directly into
the blood a solution of Na_{2}SO_{4}, which is approximately twice
as strong as a solution of this salt isosmotic with the blood would
be. Similarly a solution of MgSO_{4} isosmotic with the blood would
be about 4% (m/6 Sol^_n_ MgSO_{4} + 7 H_{2}O = 4.1 g. in 100 c.c.).
Hence the solution which Hay introduced directly into the circulation
was five times as concentrated as an isosmotic solution. Although it
is not clear just what abnormal conditions would be brought about
by the injection of such concentrated solutions, it is certain that
the normal action of the salt could not be expected under these
circumstances. This is further shown by the fact that Hay did obtain
a purgative action in some cases when he injected the salt solutions
subcutaneously. Here the injury caused by the concentrated solution was
only local, and the salt itself was absorbed in small quantities and in
more dilute solution into the blood.

In a large number of experiments which have yielded quite constant
results I have been unable to confirm the idea generally held and
supported by Hay that subcutaneous and intravenous injections of saline
purgatives do not exert a purgative action. I have quite constantly
found that with proper conditions these salts do produce increased
peristalsis and also an increased secretion of fluid into the intestine
when introduced directly into the circulation or under the skin. In
most cases also an actual passage of faeces was observed.

Several methods were used in testing the action of the salts and it was
found that the results could best be studied by observing the loops
of intestine directly. In rabbits under the influence of morphine (5
c.c. 1% solution morphine hydrochlorate subcutaneously) the abdominal
cavity was laid open and the loops of intestine carefully protected
from loss of heat and moisture while under observation. In other
cases they were observed under the surface of normal sodium chloride
solution, a method devised by van Braam-Houckgeest and used by him
in a long series of experiments. In the NaCl solution the intestines
normally remain almost quiet and the effect on them of stimulating
agents can be readily determined. In addition to this method many
experiments were made in which animals were kept in separate cages,
some acting as control animals, others for experiment. The amount and
character of the faeces were observed during several hours after the
administration of the purgative and compared with the control animals.
The solutions used were made up as fractions of molecular solutions.
Thus to obtain a solution of sodium citrate, for example, approximately
isosmotic with the rabbit’s blood, one-sixth molecular weight of the
salt in grams (including water of crystallization) was dissolved in
1,000 c.c. distilled water. This gave an m/6 solution, which was taken
to be approximately isotonic with the blood. The injections were made
usually with a hypodermic needle into the marginal vein of the rabbit’s
ear, or into the jugular vein. Subcutaneous injections were made under
the loose skin of the back. In most of these experiments small rabbits
weighing from 1,200 to 1,500 grams were used.

In studying the purgative action of these salts, two criteria may be
considered, namely, the actual passage of faeces, and secondly merely
the increase of peristalsis and secretion not necessarily accompanied
by defaecation. The former is of course the object of purgation, and
unless a salt produces an actual passage of faeces it cannot strictly
be termed a purgative. When this has been established, however, it
is of much greater advantage to use the other criterion in studying
the action of the solutions on the intestine. Any salt which in small
doses produces an increased peristalsis will with a more prolonged
action and perhaps larger doses produce actual purgation. Therefore
in the first rough test as to the action of the salts I have used the
actual passage of faeces as the criterion of the action. In this case
no morphine is given the animal and its intestines are not exposed as
in the other experiments where the movements are directly watched. In
these tests the animals were kept in boxes, the bottom of each of which
was covered by a large sheet of paper. During a certain time preceding
the injection of any solution the animals were watched and the faeces
collected and weighed. Half of the animals were kept as controls, and
the rest subjected to injections of various solutions. The average
weight of the normal faeces was compared with the weight of the faeces
passed during the same time by the animals receiving the injections.
The faeces were collected and weighed each hour during the first six
hours following the first injection. The chief purgative effect usually
took place during the first two hours. Although there was considerable
individual variation in the rabbits, there was found to be a constant
increase in the amount of faeces following the subcutaneous or
intravenous injection of one of the salts. This amount varied from two
to six times the average normal weight. Sometimes the increase was much
greater and in many cases the nature of the faeces was much changed.
The normal faeces of the rabbit consist of dry hard definitely formed
masses. Following the purgative, they become soft and unformed, and may
as in the case of NaF and BaCl_{2} be semifluid.

The amount of sodium citrate, sulphate, or tartrate necessary to
produce purgation is about the same in each case: 10 c.c. m/6 solution
injected subcutaneously, followed 10 minutes later by a second
injection of 5 c.c. of this solution and 10 minutes after this by a
third similar injection, usually produces well marked passages of
faeces. Sometimes the result is obtained with a single injection,
but a prolonged action of the salt seems to be more favorable. With
sodium fluoride and barium chloride much smaller doses are necessary.
Sodium fluoride is more poisonous than the citrate or sulphate, but
if injected slowly as much as 10 c.c. m/6 solution can be safely
introduced under the skin. This produces in a little over an hour well
marked purgation, usually with the passage of soft or semifluid faeces.
Barium chloride is a well known saline purgative among veterinary
surgeons, who always administer it intravenously or subcutaneously.
In order to purge a horse weighing 1,000 pounds, O.75 g. BaCl_{2} is
usually given subcutaneously. Its action is very constant. When given
to rabbits I have found that 2 c.c. m/6 solution BaCl_{2}, injected
under the skin always produces a well marked purgative action with
the passage of large quantities of semifluid faeces. When injected
intravenously it is better to mix the BaCl_{2} with about five times
its volume of m/6 NaCl. The injection of 1 c.c. of a mixture of 1 c.c.
m/6 BaCl_{2} + 5 c.c. m/6 NaCl produces purgation and a passage of
semifluid faeces. This action is much more rapid than with NaF.

These experiments demonstrate the fact that the intravenous or
subcutaneous injection of saline purgatives do produce purgation and
an actual passage of faeces. In order, however, to study the action of
the salts more minutely another method was resorted to, namely, that
of opening the abdomen and directly observing the loops of intestine.
In a large number of experiments it is not difficult to become quite
familiar with the movements normally present, and with the disturbances
produced by such external influences as cooling, drying, etc. These
influences can by proper precautions be practically eliminated.

By this method it was possible to study the influence of the salts
on the two great activities of the intestine, namely, the muscular
movements and the glandular activity. Their action on the secretion
is treated of in a later chapter and can only be mentioned here. The
increase of these two activities by means of a salt is the essential
action of a purgative, and leads, if sufficiently prolonged, to
purgation and to the passage of faeces. This passage of faeces does not
take place so readily when the intestines are exposed and the animal
is under the influence of morphine as it does in a normal animal. The
exposure of the intestine for an hour or more apparently renders this
action difficult, although not uncommonly the actual passage of faeces
is observed under these circumstances. This is always the case with
BaCl_{2}.

In a rabbit with its intestines visible it was found that the injection
of 1-2 c.c. m/8 or m/6 sodium citrate solution into the jugular vein
of a rabbit brings about a very marked increase in the peristaltic
movements, which begins from 1 to 2 minutes after the injection. The
loops are set in active movements and become firm and rounded so that
they seem to occupy a greater volume. The movements consist not only of
swinging pendulum movements, but of real peristaltic waves which cause
the contents of the intestine to move along the gut so that they may
be watched through the thin walls. The morphine narcosis of the animal
does not seem to interfere with this action of the salt.

When these salt solutions are administered subcutaneously they do not
act at once, as in the case of intravenous injections. An interval
of 10 to 15 minutes elapses after the subcutaneous injection before
any influence on the intestine is noticed. The movements then begin
as before, the peristaltic movements and pendulum movements gradually
increasing in force. In addition to the greater time required for the
action of the salt when administered in this way, it is also necessary
to give a larger amount than in intravenous injections; 5-10 c.c. m/8
or m/6 solution of sodium citrate must be introduced subcutaneously in
order to produce increased peristalsis.

If the solution be introduced into the stomach or intestine a similar
increase in peristalsis is brought about, but only after a considerable
interval. Usually no effect is obtained until 10 to 15 minutes after
the injection of the salt into the lumen of the gut. The injection
may be made by piercing the wall of the intestine or stomach with a
hypodermic needle, and forcing the fluid into the lumen. The quantity
of the solution necessary to produce increased peristalsis is about
the same as when introduced subcutaneously. The movements begin not
particularly in the part of the intestine containing the solution, but
simultaneously in all parts.

To any one making these experiments there can be no doubt that the
increased peristalsis is the direct result of the injection of the
salt. It can be readily proven in the following way: As will be shown
in a later chapter, the peristalsis and secretion caused by the saline
purgatives can be inhibited by the administration of calcium or
magnesium chloride. If now in a rabbit in which the intestine has been
set into active motion by the intravenous injection of sodium citrate,
a small quantity of m/6 CaCl_{2} be administered intravenously, all
of these movements cease within a minute or two. A second injection
of a slightly greater quantity of m/6 sodium citrate will overcome
this action and cause active peristalsis to begin again. These actions
cannot be due to anything but the solutions introduced.

It is evident also in watching the action of these salts that they
produce increased peristalsis much more rapidly and powerfully when
introduced intravenously than when placed in the lumen of the stomach
or intestine. A much smaller dose also is required to produce this
effect. They therefore cannot act because of their presence in the
lumen of the gut, or because of their being subsequently secreted into
the lumen. When introduced into the stomach or intestine they must
first be absorbed into the blood before they can reach the muscular and
glandular tissues upon which they act. They therefore act more slowly
and only in larger quantities when administered in this way.

Experiments similar to the above were made with a number of salts,
including sodium sulphate, fluoride, tartrate, phosphate and oxalate,
barium chloride, and magnesium sulphate. It was found that intravenous
and subcutaneous injections of all of these were active in producing a
greater or less increase in peristalsis. Sodium sulphate acted in this
respect very much as sodium citrate did. The latter, however, tended
to produce muscular twitchings in the voluntary muscles, a phenomenon
which will be spoken of later. Sodium sulphate on the other hand could
be introduced into the blood in relatively large quantities without
producing any evil effects. The action of sodium sulphate on the
intestine was found to be somewhat less than that of sodium citrate;
but almost constantly 2-3 c.c. m/6 Na_{2}SO_{4} injected into the
marginal vein of the ear caused a marked increase in the peristaltic
movements of the intestine. I cannot at all agree with Hay and earlier
writers who affirm that sodium sulphate injected intravenously produces
no purgative effect. In all my experiments I have found it to have a
very definite effect when introduced in this manner, and I can only
attribute their results to the concentrated solutions used, or to other
unfavorable conditions.

The injection of solutions of sodium fluoride produces very active
movements, although only small quantities can be administered on
account of its poisonous nature.

Barium chloride is even more poisonous and only the most minute doses
can be given. It is, however, by far the most powerful of all these
purgative salts. Its action is extremely rapid and violent. When given
intravenously it is best to mix it with about five times its volume of
m/6 NaCl solution. Thus 1 c.c. of a mixture of 5 c.c. m/6 NaCl + 1 c.c.
m/6 BaCl_{2} injected into the circulation causes almost immediately
most violent intestinal movements. The loops contract so that they
resemble white firm cords. They rise up from one another so that they
seem to stand erect and the squirming, twisting movements become
extremely active. The intestinal contents are hastened on and can be
watched through the thin walls moving rapidly from loop to loop. The
actual passage of faeces takes place in a very short time. It begins
with solid faecal masses, followed quickly by semifluid faeces. The
quantity passed is sometimes very considerable. As will be shown in a
later chapter, the injection of BaCl_{2} into the blood causes not only
an extensive increase in the peristaltic movements, but brings about
also an increase in the quantity of fluid secreted into the intestine.

The subcutaneous injection of 2-3 c.c. m/6 BaCl_{2} produces in 5-10
minutes an effect quite similar to that described for the intravenous
injection of the salt. A rabbit weighing 1,200-1,500 g. does not,
however, usually recover from a dose greater than 2.5-3 c.c. m/6
BaCl_{2} given subcutaneously, and a smaller quantity is sufficient
to produce purgation. Boehm[28] gives as the lethal dose of BaCl_{2}
when given intravenously for rabbits O.1-0.2 g., for cats 0.03-0.05 g.,
for dogs O.1-0.2 g. When given subcutaneously it is O.12-0.18 g. for
rabbits and cats and O.3 g. for dogs.

When BaCl_{2} is taken into the stomach it is absorbed quite slowly,
but its effects are similar to those described above. Active
peristaltic movements and purgation result, and in many cases vomiting
is seen in dogs.

It is clear from these experiments that all salts do not act equally on
the intestine. Sodium chloride may be introduced in large quantities
into the circulation without causing increased peristalsis or
defaecation. Sodium oxalate and phosphate (Na_{2}HPO_{4}) exert only
a slight action. Sodium phosphate, according to Bunge, increases the
fluid in the intestine. Sodium tartrate produces quite active movements
of the intestine and is considerably stronger in its action than either
the oxalate or phosphate. Sodium citrate and sulphate as described
above are quite constant and vigorous in their action, while barium
chloride is by far the most powerful of all these saline purgatives.
Sodium fluoride also acts very rapidly.

In addition to their action on the intestine, some of these salts
affect the salivary gland. After the injection of BaCl_{2} there is
often so great a flow of saliva that it falls in drops from the mouth.
This phenomenon is not constant, however, and seems to follow only
large doses. Sodium fluoride has sometimes the same effect. I have
not noticed any influence exerted by the other purgative salts upon
the salivary secretion. It is further of not infrequent occurrence
to have a repeated evacuation of urine after the administration of
BaCl_{2}. Although this cannot be attributed to a direct increase of
the secretion of urine, it is interesting to note in this connection
some later experiments in which it was shown[29] that when the flow of
urine in a rabbit had been well established by the injection of m/6
NaCl solution into the circulation, the addition of a minute quantity
of BaCl_{2} to the NaCl solution caused a very considerable increase
in the secretion of urine from the kidney. A quantity of not more
than ¹⁄₈ c.c. m/8 BaCl_{2}, must be given intravenously to produce
this effect. If 1 c.c. m/8 BaCl_{2} be injected intravenously at one
time the flow of urine suddenly stops. This seems to be due either to
a sudden constriction of the musculature of the urinary passages and
pelvis of the kidney by which the lumen is cut off, or to a similar
constriction of the blood vessels of the kidney. In either case the
action of BaCl_{2} in stopping the secretion is mechanical and has
to do with its power of causing violent muscular contractions rather
than with its capacity for increasing the secretory activity. Although
there is apparently one action for BaCl_{2} on the flow of urine when
given in small doses and quite the opposite action when it is given in
larger quantities, the two actions are in reality quite distinct, one
being exerted on the secretory cells of the kidney and the other on the
musculature of either the urinary passages or of the blood vessels of
the kidney.

In addition to their action on the intestine and in some cases the
kidney and salivary gland, these salts produce an interesting condition
of the voluntary muscles. As mentioned above, Loeb was able to produce
muscular twitchings in the muscle of a frog by immersing the muscle in
solutions of these various salts. He also produced muscular twitching
in a living frog by injecting sodium citrate into the dorsal lymph
sacs. I have found that a subcutaneous injection of 10 c.c. m/1 sodium
citrate produces in a rabbit well marked twitchings of the muscles all
over the body. These are very noticeable in the gluteal region. They
begin almost immediately in the neighborhood of the injection, but
only after an interval of 20 to 25 minutes on the opposite side of the
body. If the animal be placed on the floor it moves with a peculiar
incoördinated gait. The hind legs are dragged and very little headway
is made. If the rabbit be held up by the ears, the feet tremble, and if
touched the legs jerk away violently and usually become rigid. There
are sometimes tetanus-like contractions of the limbs, and occasionally
general convulsions of greater or less severity. In one rabbit I gave
daily injections of 5 c.c. m/1 sodium citrate subcutaneously throughout
one month. For some time after the injections had been discontinued
the hypersensitiveness seemed to persist. It seemed possible from this
that a chronic state of increased irritability might be produced.
No conclusion, however, can be drawn from this one experiment since
the irritation caused by the repeated injections might have had some
influence. It is a subject which is of interest for further experiment,
on account of the similarity such a chronic condition bears to the
various chronic hypersensitive conditions found in human beings.

In looking over the experiments made by various investigators on this
subject it will be noticed that their results are inconstant and
contradictory. This can only be the result of imperfect technique and
unfavorable conditions, or of the adoption of a criterion of the action
of the salt, which is uncertain. As mentioned above, the solutions used
in many cases were not at all those most favorable for introduction
into the blood. The very concentrated solutions used by Hay rendered
the conditions obviously unfavorable. If in addition to watching for
the actual passage of faeces these experimenters had observed the
intestines directly the results would of necessity have been more
uniform.

My own experiments have given quite uniform results, so much so that
the production of increased peristalsis in rabbits by the intravenous
injection of one of the saline purgatives has come to be a class
experiment with the students in the medical school here. The increased
secretion into the intestine produced by the same means requires
greater care in protecting the loops from loss of heat and moisture.
For any one to convince himself that a salt may act as a purgative
when injected subcutaneously or intravenously it is only necessary to
introduce a small amount of BaCl_{2} into the blood or under the skin
of a rabbit. The evacuation of large quantities of semifluid faeces
and the violent intestinal movements leave no room for doubt as to the
action of the salt. The fact that the intravenous and subcutaneous
administration of this salt as a purgative by veterinarians is in
general use should be sufficient proof.

The milder salts such as sodium citrate and sulphate must, as stated
above, be given in larger quantities, and a more prolonged action is
necessary.

As will be described in detail in the next chapter, the application of
solutions of these salts, isosmotic with the blood, to the peritoneal
surfaces of the intestine cause not only increased peristalsis and
increased secretion of fluid into the intestine but also bring about an
evacuation of faeces. This fact alone proves that it is not necessary
to introduce the purgative salt into the stomach or intestine. The
action on the intestine in this case takes place more rapidly than in
any other method of administration. The solution seems to be directly
absorbed through the peritoneal covering and to come into contact with
the muscles and glands, and perhaps the nerves of the intestine. These
tissues are immediately set into activity.

In the intravenous or subcutaneous injections of the salts it is
necessary to mention a peculiarity of magnesium sulphate. This salt of
course acts as a purgative because it is a sulphate and not on account
of the presence of magnesium. As shown later on, magnesium chloride has
an effect quite opposite to this. In injecting MgSO_{4} into the blood
the greatest care must be taken because of its peculiarly poisonous
nature when rapidly absorbed. Rabbits frequently die suddenly from an
injection of a relatively small quantity. This fact has been mentioned
by a number of authors, and is repeated here only as a warning against
its too rapid injection, possibly in human beings.

It may be mentioned here also that Bottazzi[30] has found that the
intravenous injection of an extract of the small intestine containing
secretin causes not only a well marked increase in the secretion of
fluid into the intestine, but also produces increased peristaltic
activity. It at the same time increases the pancreatic secretion.


FOOTNOTES:

[22] Leçons sur les effets des substances toxiques et médicamenteuses,
Paris, 1857.

[23] Arch. f. physiol. Heilkunde, 1854.

[24] Gaz. Méd. de Paris, 1879.

[25] Action of Medicines, 1867.

[26] Gazette Médicale, 1873.

[27] Journal of Anatomy and Physiology, Vol. XVI, 1882, and XVII, 1883.

[28] Arch. f. exp. Path. u. Pharm., Bd. 3, 1875, p. 215.

[29] MACCALLUM, J. B.: Journal of Exp. Zoology, Vol. I, No. 1, 1904.
Preliminary Report, University of California Publications, Physiology,
Vol. I, No. 10, p. 81, 1904.

[30] Arch. di Fisiologia, 1904, I, 413.




                             CHAPTER III.

The Local Application of Saline Solutions to the Peritoneal Surfaces of
                            the Intestine.


In the last chapter it has been shown that the subcutaneous and
intravenous injections of solutions of various saline purgatives
produce a characteristic purgative effect; and that similar injections
of calcium or magnesium chloride inhibit this action and bring the
intestines to rest.

I have found also that solutions of these salts have the same effect
when applied directly to the peritoneal surface of the intestine. Thus
if a solution of sodium citrate or sulphate,[31] for example, be poured
over the intestine those loops which are moistened by the solution will
become active within one minute. After a very short time the remaining
loops are also set in motion. These movements may be entirely inhibited
by pouring on the loops a solution of calcium or magnesium chloride.
The following description of these experiments is taken directly from
my paper which appeared two years ago.[32]

The intestines of a rabbit under the influence of morphine were
exposed. On a small group of coils there were poured 3 c.c. m/6 sodium
citrate solution. Almost immediately (within 1 minute) the loops became
very active. Strong contractions of the muscle coats took place. After
a few minutes the other loops were also set in movement, so that the
whole small intestine showed active peristalsis. The citrate solution
was then washed off by m/6 NaCl solution, and about 3 c.c. m/6 CaCl_{2}
solution poured on the loops. The peristaltic movements were promptly
suppressed, and the intestine remained quiet. By the further addition
of citrate solution, the coils were set in active movement once more,
and by the subsequent application of calcium chloride solution again
inhibited. This was repeated many times (sixteen) and apparently might
have been continued as long as the intestine remained alive.

The same results were obtained by using instead of the sodium citrate
solution, a solution of barium chloride, sodium sulphate, fluoride,
bromide, iodide, phosphate (Na_{3}PO_{4}), oxalate or tartrate. Local
application of solutions of any of these salts produces increased
peristaltic activity. Solutions of sodium chloride have a very slight
action of the same character. On the other hand, the intestinal
movements are equally inhibited by calcium chloride and magnesium
chloride, while strontium chloride has a similar but less powerful
inhibiting action.

In testing those salts with which it was necessary to use dilutions
greater than m/8, the dilution was made with a neutral fluid consisting
of sodium chloride and magnesium chloride. It was found that m/6 NaCl
solution increased to a very slight extent the peristaltic movements.
By adding to 10 c.c. m/6 NaCl, 0.5 c.c. m/6 MgCl_{2}, a fluid was
obtained which had apparently neither stimulating nor inhibiting
effects. In addition to solutions made up by dilution with this neutral
fluid, others were used in which the salt solutions were diluted with
distilled water. Practically the same results were obtained in both
cases. It was found that 1 c.c. m/320 BaCl_{2} solution applied locally
to the intestine is sufficient to cause strong peristaltic movements in
a rabbit. This quantity contains about 0.00076 gm. barium chloride.
In the case of sodium citrate, the concentration must be considerably
greater. No solution of this salt more dilute than m/80 is active in a
rabbit. Of all the purgative salts, barium chloride is by far the most
powerful. If a drop of m/8 BaCl_{2} be placed on the serous surface of
an intestinal loop, or if a small area be moistened with this solution
by means of a camel’s hair brush, the muscle beneath the moistened
area will almost immediately contract so that a ring-like constriction
of the intestine is formed. This often is so sharply marked that it
suggests the effect produced by tying a ligature around the intestine.
This constriction remains for a few moments, and then gradually moves
along the loop in the direction of the normal peristalsis. If the
solution be injected into the muscle of the intestine at any point
with a hypodermic needle, a similar sharp constriction takes place. If
also a few drops be injected directly into a branch of the superior
mesenteric artery, all that part of the loop supplied by the arterial
branch will contract violently. These statements are true also in the
case of sodium citrate, fluoride, sulphate, etc.; the action of these
salts, however, is less powerful.

It must be added here also that the actual passage of faeces may be
produced within an hour by the application of the purgative salts to
the serous surfaces of the intestine. This takes place most quickly
with barium chloride. It is possible to observe directly through the
semi-transparent walls of the intestine the rapid passage of faecal
masses from one loop to another.

The intestines of the rabbit are apparently much more sensitive to the
action of sodium citrate and sulphate than are those of the dog or
cat. Barium chloride, on the contrary, acts with equal strength in all
these animals. In a rabbit, the intestines are always set in active
peristaltic movement by contact with m/8 sodium citrate solution;
and even much more dilute solutions are, as a rule, effective. In a
cat, however, it was found that an m/8 solution of sodium citrate
has practically no effect, while a ⁵⁄₈m solution sets the intestine
in active motion. In a dog also m/8 sodium citrate solution is
usually ineffective. Similarly an m/8 sodium sulphate solution is
inactive in a dog while an m/2 solution of the same salt starts up
distinct peristalsis. In the cat and dog also the peristalsis may be
inhibited by calcium or magnesium chloride, as shown in the following
experiments. The intestines of a cat were exposed in the usual manner,
and an m/8 solution of sodium citrate was applied to the serous surface
of the loops. There was no increased movement. There were then poured
on the loops a few cubic centimetres of a mixture of 5 c.c. ⁵⁄₈m sodium
citrate and 5 c.c. ⁵⁄₈m CaCl_{2}. The loops remained motionless.
After waiting a considerable time (15 minutes), a ⁵⁄₈m solution of
sodium citrate alone was poured on the intestine. Almost immediately
they became very active; and the peristalsis continued until calcium
chloride was again applied. The loops then came to a standstill. The
difference in susceptibility to the action of citrate which exists
between rabbits on the one hand, and dogs and cats on the other, may
be in some way connected with their being herbivorous and carnivorous
animals respectively.

The action of the sodium citrate, sulphate, fluoride, etc., when
applied locally, may be inhibited by the administration of an
approximately equal quantity of calcium or magnesium chloride of
the same concentration. The counteraction of the effect of barium
chloride, however, requires a much greater concentration of calcium.
Using equal quantities of the two salts, the action of the barium is
usually not inhibited, a fact which I have previously stated. With
greater concentrations of the calcium chloride, the antagonistic
action, however, is clear. This is shown in the following experiment:
Applied locally to the intestine of a rabbit 1 c.c. m/320 BaCl_{2}
solution caused active peristaltic movements. The application of 1
c.c. m/320 CaCl_{2} solution exercised no inhibiting effect whatever.
The same quantity of m/40 CaCl_{2} was then poured on the loops, and
a slight but distinct quieting of the loops took place. The addition
of 1 c.c. m/6 CaCl_{2} caused the loops to become entirely motionless.
After waiting a considerable time, 1 c.c. m/8 BaCl_{2} was poured
on the intestine. Immediately violent peristaltic movements took
place. Several c.c. m/6 CaCl_{2} exercised practically no inhibiting
influence; while 2 c.c. ⁵⁄₈m CaCl_{2} solution suppressed the movements
entirely for a short time.

The question concerning the exact seat of action of the purgative
salts remains still unanswered. Whether, upon being absorbed into the
blood, they act on the central nervous system is not known. There is
no evidence to show that this is the case. It seems certain, on the
other hand, from the experiments here described, that they undoubtedly
have a peripheral action either on the peripheral nervous mechanism or
on the muscle cells themselves. It is impossible to prove that there
is no action on the central nervous system, and at present it seems
impossible to prove whether the peripheral action is directly on the
nerves or on the muscles. The existence in the walls of the intestine
of the ganglionic plexuses of Auerbach and Meissner must be taken
into consideration; and with the methods available there seems to be
no way of distinguishing the action on these plexuses and the direct
action on the muscle cells. The ultimate effect is on the muscles and
glands; and the fact that an entirely local ring-shaped constriction
can be brought about by the local application of a drop of one of the
salt solutions to the surface of the intestine would seem to indicate
that only a small group of the circular muscle fibres themselves is
affected. The fact that the nerve plexuses form a continuous network,
and are intimately related in their various parts, would suggest that
the occurrence of an action on these plexuses confined to so small an
area is improbable. The discussion of the exact location of the action
is, however, of relatively little importance, as compared with the
main facts shown by these experiments, namely, that _it is possible to
produce, by the local application of a purgative salt to the serous
surface of the intestine, a striking increase in peristalsis, and to
suppress these movements by a similar application of solutions of
calcium, magnesium, or strontium chloride_.

These experiments also seem to decide the question as to whether the
salt solutions act after being absorbed into the blood or only when
placed in the intestine. According to Hay[33] and others, the salt
which is absorbed into the circulation has no effect and the only
action is produced by that which remains in the intestine. This is
obviously not true since the solutions act much more rapidly and more
powerfully when applied to the outside of the intestine, _i.e._, to
the peritoneal surface. No action is observed until after an interval
of 10 to 15 minutes after the salt solution is placed in the lumen of
the intestine, while application of the same solution to the peritoneal
surface causes movements of the intestine within one minute.


FOOTNOTES:

[31] Pohl (Arch. f. exp. Path. u. Pharm., Bd. 34, S. 87) stated that
all sodium and ammonium salts increased the peristalsis when applied to
the peritoneal surface of the intestine.

[32] MACCALLUM, J. B.: Amer. Journ. Physiol., Vol. X, No. V, 1904, p.
259.

[33] _Loc. cit._




                              CHAPTER IV.

 The Production of Increased Secretion of Fluid into the Intestine by
                        the Saline Purgatives.


One of the most characteristic things to be observed in purgation is
the presence of a greater quantity of fluid in the stools. This varies
in degree with the different drugs, but even with the mild laxatives
the faeces become less solid. With the stronger purgatives they become
quite fluid. Since the earliest attempts to explain the nature of
purgation there has been the question as to the origin of this fluid.
With the discovery of the property of osmosis in salts a new life was
given to this inquiry, and Poiseuille[34] advanced the theory that the
purgative effect of salts was due entirely to their endosmotic power,
the increased fluid of the faeces being caused by the extraction of
fluid from the tissues by the osmotic power of the salt. The same
view was held by Liebig,[35] whose name is commonly associated with
the hypothesis. Rabuteau[36] later on supported this idea and claimed
as proof of it the fact that he was unable to produce purgation by
the intravenous injection of large quantities of sodium sulphate. He
even found that this injection caused constipation, and he concluded
that since sodium sulphate purges when given by mouth there must be
caused a flow of fluid towards the salt in both cases. This osmosis
theory was attacked by Claude Bernard,[37] who pointed out that if
the purgative action of salts were due to their osmotic power, sugar
must also be a strong purgative. He found further that, contrary to
what Rabuteau stated, intravenous injections of sodium sulphate do
cause purgation and bring it about more rapidly and powerfully than
when the salt is taken by mouth. It was further shown by Aubert[38]
that the purgative effect of various salts is not at all proportional
to their endosmotic power nor to their concentration. Headland,[39]
assuming without experiment that purgative salts act when introduced
into the circulation, advanced the hypothesis that when they are given
by mouth they are first absorbed into the blood and are later excreted
by the intestine. In thus passing through the intestine he supposed
that they stimulated the glands to secrete. Brieger,[40] using the
method introduced by Colin and Moreau, obtained what he considered
an increased secretion into the intestine. Isolating a loop of the
intestine, he introduced into it a strong solution of MgSO_{4}. The
loop became in a short time filled with a clear yellow alkaline fluid.
This he believed was due partly to the water attracting power of the
salt, and partly to the production of a real secretion. Vulpian[41]
believed that the fluid was due to an inflammatory irritation. Hay[42]
made experiments similar to those of Brieger, and found that the
introduction into a loop of 10% Na_{2}SO_{4}, caused a considerable
increase in the secretion, although no secretion was obtained by a 1-5%
solution. Schmiedeberg[43] explained the presence of a greater quantity
of fluid in the stools following the administration of the purgative
by the supposition that the purgative salts on reaching the large
intestine prevent the absorption of water. He states that these salts
are themselves absorbed with difficulty and hence reach the lower part
of the intestine unchanged. A similar hypothesis is advanced by Wallace
and Cushny.[44] They stated that the absorption of fluid was inhibited
especially by those salts which form insoluble compounds with calcium.
These authors, however, did not take into account the possibility of
the secretion of fluid into the intestine being increased by these
salts. Hence their method of determining the difference in absorption
of the various solutions is open to criticism, since it will be shown
in this chapter that some if not all of these purgative salts cause a
very definite increase in the intestinal fluid. The absorption of fluid
may indeed be diminished by these salts, but it is difficult to say in
the experiments of Wallace and Cushny how much of the fluid remaining
in the loops is due to inhibited absorption, and how much has been
actually secreted by the intestine.

The experiments of Brieger[45] and Hay[46] in the production of
increased secretion are quite unsatisfactory on account of the great
concentration of the solutions used. Their results may well be ascribed
to the local irritating effect of the strong solution, since they did
not obtain an increased secretion with weaker solutions.

As stated above in a previous section, I have made a large number
of experiments to determine whether or not an increased secretion
is actually caused by the saline purgatives, and have found by
measurements that with some of the salts this increase is very marked.
These results have been already published,[47] and the tables and
a part of the description given below are taken from this paper.
Rabbits and dogs were used in these experiments. In the case of the
rabbits anaesthesia was produced by the subcutaneous injection of
4-5 c.c. 1% morphine hydrochlorate. The rabbits were not full grown,
their average weight being not more than 1,200 g. The same amount of
morphine was given also to the dogs, and was supplemented by ether. The
abdominal cavity was opened and a loop of considerable length tied off
with ligatures. In the rabbit the upper part of the small intestine
was selected and the upper ligature placed just below the entrance
of the common bile duct. The second ligature was tied 25 to 30 cm.
lower down. At the lower end of the loop a large mouthed cannula was
inserted from which the fluid could be drained by gently lifting the
successive parts of the loop, a process made more easy by placing the
animal board at a considerable angle with the table. All of this was
done as rapidly as possible, so that the loops would be exposed as
little as possible to the air. After the loop had been emptied of what
it contained in this way, the intestines were covered over with filter
paper soaked in warm m/6 NaCl solution, and this again covered with a
towel wet with warm water, and over it all a woolen cloth. In this way
the loops were protected fairly well from drying and loss of heat. The
contact with the wet filter paper did not seem in any way to affect the
intestine. Other experiments were made with the filter paper raised
from the intestine by a wire tent. I found that if these precautions
against loss of heat and drying were neglected the secretion did not
take place. The greatest care must be exercised in this respect since
the slightest cooling seems to inhibit the secretory activity of the
intestine.

The loop which had thus been emptied and returned to moist warm
surroundings was left 10 minutes and the normal secretion allowed to
collect, and at the end of that period the loop was again emptied with
as little exposure as possible and the fluid measured. The cannula
was then clamped off and the secretion allowed to gather for a second
10 minutes. This again was drawn off and measured. The quantity
secreted was usually fairly constant and quite small, the manipulation
undoubtedly increasing it somewhat. When the normal secretion was
obtained the purgative salt in an isotonic solution was administered
either subcutaneously, intravenously, or locally. The secretion was
again allowed to collect, and was drained off and measured after 10
minutes. This was repeated several times and the amounts compared with
what was taken as the normal secretion. When the solution was applied
locally, a method which is perhaps the most satisfactory, it was
allowed to drop on the loops from a pipette, care being taken to have
it at body temperature and as nearly as possible isosmotic with the
blood. In each case special care was taken to have no interval between
the emptying of the loop and the beginning of the succeeding period of
10 minutes. In other words, the loop was always entirely empty at the
beginning of each period.

The results of a few of these experiments may be seen in the following
reports:--

  1. Rabbit. Loop 30 cm. long, upper part of small intestine.

  Loop contained in beginning[48]                              5.0 c.c.
  Fluid removed after 1st 10 minutes                           0.2 c.c.
  Fluid removed after 2d 10 minutes                            0.5 c.c.

  2 c.c. m/8 BaCl_{2}, injected subcutaneously.

  Fluid removed after 1st 10 minutes following injection       4.0 c.c.
  Fluid removed after 2d 10 minutes following injection        3.4 c.c.
  Fluid removed after 3d 10 minutes following injection        3.0 c.c.

In this rabbit the increased secretion of fluid was accompanied by
extremely active peristaltic movements. The faeces could be seen
passing along the loops of the lower part of the intestine with great
rapidity. Within 30 minutes after the administration of the salt, the
passage of faeces to the outside began. This continued for some time,
the faeces becoming constantly softer, until finally they were almost
entirely unformed.

As shown by this experiment, and also by the following ones, the action
of barium chloride persists for a considerable length of time. The
action of sodium citrate is more transitory.

  2. Rabbit. Loop 25 cm. long.

  Loop contained in beginning   3.0 c.c. fluid deeply bile stained
  After 1st 10 minutes          1.0 c.c. fluid deeply bile stained
  After 2d 10 minutes           0.8 c.c. fluid somewhat lighter in color

  Injected 2 c.c. m/8 BaCl_{2} solution subcutaneously.
  After 1st 10 min. following injection 2.5 c.c. fluid light yellow
  After 2d 10 min. following injection  1.6 c.c. fluid very light yellow
  After 3d 10 min. following injection  1.8 c.c. fluid almost colorless
  After 4th 10 min. following injection 1.6 c.c. fluid quite colorless

  After 5th 10 min. following
  injection 1.0 c.c. fluid quite colorless

  3. Rabbit. Loop 32 cm. long.

  Loop contained in beginning                                  6.0 c.c.
  After 1st 10 minutes                                         0.4 c.c.
  After 2d 10 minutes                                          0.1 c.c.
  After 3d 10 minutes                                          0.4 c.c.

  Poured 5 c.c. m/8 sodium citrate on loop.
  After 1st 10 minutes                                         6.2 c.c.
  After 2d 10 minutes                                          2.0 c.c.

  4. Dog. Loop 35 cm. long.

  Loop contained no fluid, _i.e._, none could be drained off.
  After 1st 10 minutes                                         0.0 c.c.
  After 2d 10 minutes                                          0.0 c.c.
  After 3d 10 minutes                                          0.0 c.c.

  Poured 3 c.c. m/8 BaCl_{2} on loop.
  After 1st 20 minutes                                         8.0 c.c.
  After 2d 20 minutes                                          0.6 c.c.

  Poured 1¹⁄₂ c.c. m/8 BaCl_{2} on loop just enough to moisten it.
  After 1st 20 minutes                                         3.2 c.c.
  After 2d 20 minutes                                          2.5 c.c.

From these experiments, in which every precaution was taken, it seems
certain that a definite increase in the secretion of fluid into the
intestine follows the administration of barium chloride, and sodium
citrate, the former of which is a saline purgative of a more powerful
type, while the latter is among the milder purgative salts. It is of
especial interest that these salts do not produce the increase of
fluid on account of an irritating effect on the mucous membrane of
the intestine. The action takes place, as shown in the experiments,
when they are introduced subcutaneously or directly applied to the
peritoneal surface of the intestine. Further, the solutions were
practically isosmotic with the blood, and for this reason and from the
fact that they were applied to the peritoneal surface of the intestine
the osmotic pressure of the solution could play no part in causing
fluid to enter the lumen of the gut. Also it is obvious that any
possible effect which the purgatives may have in delaying absorption
from the intestine (Wallace and Cushny) could have nothing to do
with the production of this increased amount of fluid in the loops
experimented with. The fluid produced is clear and either colorless or
slightly yellow. It has an alkaline reaction and is apparently quite
similar to the normal intestinal secretion. I have made no experiments
to determine its powers of digesting and have no data concerning this
point. There are no signs of its being of an inflammatory nature.

Thinking that the manipulation of the intestine and the tying off of
loops might influence the results, I estimated from the examination
of a large number of rabbits of the same size (about 1,200 g. in
weight) the quantity of fluid which is normally found in the small
intestine. It was found that there was hardly ever more than 10 c.c.,
and usually only 5 or 6 c.c. of fluid in addition to a small amount of
semifluid food material. To a rabbit in which the intestines seemed
almost empty, a small dose of barium chloride was given locally by
pouring an m/8 solution on the loops. The characteristic effect of the
barium followed, and after one hour the small intestine was tied off
by ligatures and removed. It was found to contain 22 c.c. of a clear
yellowish fluid. In a second rabbit which received the same treatment
34 c.c. of a similar fluid were found in the small intestine.

As will be shown in a later chapter, a secretion of fluid into the
lumen of isolated loops of intestine removed from the body may be
produced by immersing the loops, with their ends tied, in solutions
of various saline purgatives. In m/8 solutions of NaCl, Na_{2}SO_{4},
and sodium citrate no secretion was obtained in these loops. In m/2
solution of these salts, however, a distinct measurable quantity was
regularly produced; m/8 solutions of NaF brought about a secretion, and
in all solutions containing BaCl_{2} a distinct secretion of fluid was
obtained. This will be described in detail later on.

As stated above, Bottazzi has found that an extract of the small
intestine, which increases the secretion of pancreatic juice, is
capable also when injected intravenously of increasing not only the
secretory activity of the intestine, but also its peristalsis.

As stated in detail in another chapter, the secretion of fluid into the
intestine, as well as the peristaltic movements, is inhibited by the
administration of calcium or magnesium chloride. This is illustrated by
the following experiments:--

  1. Rabbit. Loop 23 cm. long.

  Loop contained in beginning                                  0.9 c.c.
  Fluid secreted during 1st 10 minutes                         0.7 c.c.
  Fluid secreted during 2d 10 minutes                          0.6 c.c.

  2 c.c. m/8 CaCl_{2} applied locally.
  Fluid secreted during 1st 10 minutes                        0.15 c.c.
  Fluid secreted during 2d 10 minutes                          0.0 c.c.
  Fluid secreted during 3d 10 minutes                          0.0 c.c.

  4 c.c. m/8 sodium citrate applied locally.
  Fluid secreted during 1st 10 minutes                         0.4 c.c.
  Fluid secreted during 2d 10 minutes                          0.2 c.c.

  2. Rabbit. Loop 25 cm. long.

  Loop contained in beginning                                  2.0 c.c.
  Fluid secreted during 1st 10 minutes                         0.8 c.c.
  Fluid secreted during 2d 10 minutes                          0.4 c.c.

  2 c.c. m/8 CaCl_{2} applied locally to serous surface.
  Fluid secreted during 1st 10 minutes following application   0.0 c.c.
  Fluid secreted during 2d 10 minutes following application    0.0 c.c.

  4 c.c. m/8 sodium citrate applied locally.
  Fluid secreted during 1st 10 minutes                         0.6 c.c.

  3. Rabbit. Loop 22 cm. long.

  Loop contained in beginning                                  2.4 c.c.
  Fluid secreted during 1st 10 minutes                         1.2 c.c.
  Fluid secreted during 2d 10 minutes                         1.15 c.c.

  3 c.c. m/8 MgCl_{2} applied locally to serous surface.
  Fluid secreted during 1st 10 minutes following application   0.0 c.c.
  Fluid secreted during 2d 10 minutes following application    0.0 c.c.
  Fluid secreted during 3d 10 minutes following application    0.2 c.c.

Although in these experiments the quantity of fluid secreted is
small, there is a definite cessation of this excretion following
the application of calcium or magnesium chloride. The subsequent
administration of sodium citrate in each case causes the secretion to
recommence.


FOOTNOTES:

[34] Recherch. expériment. sur les mouvements des liquides dans les
tubes de petits diamètres, Paris, 1828. Comptes rendus t. 19, 1844.
Quoted from Hay.

[35] Über die Saftbewegung, 1848.

[36] L’Union Médicale, 1871, Nos. 50 et 52. Gaz. Méd. de Paris, 1879.

[37] Leçons sur les effets des substances toxiques et médicamenteuses,
Paris, 1857.

[38] Zeitsch. f. Rationelle Medicin, Bd. I, 1851.

[39] Action of Medicines, 1857.

[40] Archiv f. exp. Path. u. Pharm., Bd. VIII, 1878, S. 355.

[41] Gazette Médicale, 1873.

[42] Journal of Physiology, Vol. XVI, 1882.

[43] Arzneimittellehre, Leipzig, 1883.

[44] Amer. Journ. Physiol., Vol. I, 1898, p. 411.

[45] _Loc. cit._

[46] _Loc. cit._

[47] Amer. Journ. Physiol., Vol. X, 1904, p. 209.

[48] In all these experiments there was no interval between the
emptying of the loop and the beginning of the 10-minute period which
followed. The injections were made as rapidly as possible, and in no
case occupied more than a minute.




                              CHAPTER V.

  The Inhibiting Action of Calcium and Magnesium on the Movements and
                      Secretion of the Intestine.


It was first observed by Ringer[49] that the unfavorable effect
produced by pure NaCl solution could be lessened by adding other
salts, notably calcium and potassium. From this observation there was
made the so-called Ringer’s solution, which contains Na, K, and Ca in
proportions which render the solution relatively neutral and innocuous
towards the living tissues.

Howell,[50] working with the heart of the terrapin in various mixtures
of Na, K, and Ca chloride, emphasized the importance of calcium in
the medium in which the heart beat. He concluded from his experiments
that the sodium chloride was mainly instrumental in establishing and
maintaining the proper osmotic conditions, while calcium was the main
factor in initiating and maintaining the beat of the heart. To quote
from his articles:--“The stimulus that leads to a heart contraction
is dependent upon the presence of calcium compounds in the liquids of
the heart; but for rhythmic contractions and relaxations a certain
proportion of potassium compounds is necessary.” “The sodium chloride
seems to be essential only in preserving the osmotic relations between
the tissues and the surrounding liquid.” Similar conclusions were
arrived at by Green.[51]

Loeb,[52] working with Gonionemus, and with the striated muscles of
the frog, arrived at conclusions which are in some respects entirely
opposed to those of Howell. What Loeb spoke of as the toxic effects of
sodium chloride was emphasized by this work. This was especially shown
in the case of Fundulus eggs which, though freshly fertilized, cannot
develop in pure NaCl solution, although they develop in sea-water or
in distilled water. In this case the addition of a small quantity of
calcium chloride to the NaCl rendered development possible. According
to Loeb, the Ca exerted an antitoxic effect and neutralized the
injurious action of the NaCl. Similarly it was found that the apex
of the heart contracts rhythmically in a pure NaCl solution, but
soon came to a standstill. The addition of a small amount of calcium
is sufficient to cause the contractions to persist for a long time.
This again was referred to the toxic and antitoxic effects of the
salts. From these and similar experiments arose the conception of
“physiologically balanced solutions” in which the toxic effect of each
substance in the solution is exactly counteracted by the antitoxic
effect of some other substance in the same solution.

Other experiments by Loeb showed that if the voluntary muscle of a
frog be immersed in a pure NaCl solution, rhythmical twitchings appear
which continue for many hours, or even for days. If, however, a small
quantity of CaCl_{2} be added to the NaCl solution the twitchings
cease, although the muscle remains alive in this mixture longer than it
does in pure NaCl. Similar results were obtained with solutions of the
sodium salts which precipitate calcium, fluoride, oxalate, carbonate,
phosphate, etc. In all of these solutions twitchings developed in the
muscle. Magnesium and strontium act like calcium in inhibiting the
muscular twitchings produced by sodium salts. These experiments led
Loeb to the conclusion that the presence of calcium in the body keeps
the voluntary muscles from constantly twitching or beating rhythmically
in the way the heart does. Calcium, magnesium, and strontium seemed to
have a definite inhibitory action on the muscular contractions.

Loeb further showed that the center of a jellyfish (Gonionemus), which
when isolated from the margin will not contract in sea-water, will beat
rhythmically if placed in pure NaCl solution. If a quantity of CaCl_{2}
or Ca(NO_{3})_{2} be added to the NaCl solution the contractions
are inhibited. Magnesium and strontium behave in this respect like
calcium. If also a sufficient quantity of a calcium precipitating
solution (sodium fluoride, phosphate, etc.) be added to sea-water in
which the center will not beat, rhythmical contractions soon appear,
due apparently to the removal of the calcium from the sea-water and
the tissue. In these experiments, as in those with voluntary muscles,
calcium, magnesium and strontium have apparently an inhibiting action
on muscular contractions.

Loeb has recently made experiments on a jellyfish of the Pacific
(Polyorchis) with results which are somewhat different from those
described for voluntary muscles and Gonionemus. He found that the
normal swimming movements of the uninjured animal could not occur in
solutions which did not contain some proportion of magnesium, and
the presence of magnesium in the sea-water seemed to be the stimulus
for the apparently spontaneous movements of the animal. Calcium and
potassium were found to oppose this action of magnesium. Further with
the isolated center of Polyorchis, which will not beat in pure sugar
solution or in sea-water, it was found that the addition of CaCl_{2},
SrCl_{2}, or BaCl_{2} to either solution caused contractions to appear.
Magnesium chloride did not produce this effect. In pure NaCl solution
also the isolated center will not beat, or beats only after a long
time, while the addition of CaCl_{2} to the NaCl causes it to beat at
once.

Lingle[53] made experiments with the ventricle of the tortoise heart,
which was able to beat for only a short time in pure NaCl solutions.
When a small amount of CaCl_{2} is added, however, the heart may
continue to beat for a long period. Lingle explained this by the
assumption that NaCl is a poison and that calcium acts in an antitoxic
way, a suggestion already offered by Loeb.

Loeb’s experiments on the inhibition of muscular twitchings in
voluntary muscles by calcium and magnesium, as well as the similar
results he obtained with the isolated center of Gonionemus, led me to
test the action of these two substances on the rhythmical movements
of the mammalian intestine. It was found that not only the normal
movements of the intestine, but also those produced by the saline
purgatives such as sodium citrate, sulphate, tartrate, etc., could be
very definitely inhibited by the administration of calcium or magnesium
chloride. This was the case when these latter substances were given in
any way either intravenously, subcutaneously, or applied directly to
the serous surfaces of the intestine. The following experiments will
illustrate this inhibitory action.

A rabbit was anaesthetized by a subcutaneous injection of 4-5 c.c.
1% morphine solution. The intestines were then carefully exposed and
protected in every way from loss of heat and moisture. The method
suggested by van Braam-Houckgeest[54] of opening the abdomen under the
surface of sodium chloride solution is perhaps the most perfect. A
small quantity of m/6 sodium citrate solution (for a rabbit weighing
1,200 g. 2-3 c.c. is sufficient) was injected into a vein of the ear.
The intestines almost immediately began to move actively. There was
then injected 3-4 c.c. m/6 CaCl_{2} solution. The intestines within
2 or 3 minutes came entirely to rest and remained perfectly quiet.
A second injection of a somewhat greater quantity of sodium citrate
caused them to again become active.

A still more striking experiment may be made by exposing the
intestines and pouring a small quantity of sodium citrate solution on
their peritoneal surfaces. Immediately they become extremely active. If
now they be washed off with a little NaCl solution and a few c.c. of a
solution of calcium chloride be poured on them they will come to rest
at once. These solutions must be at body temperature and isotonic with
the blood. If the loops which have been quieted by CaCl_{2} are again
moistened with the citrate solution they will be set into motion as
before, and a subsequent application of CaCl_{2} will again cause all
movement to cease. This may be continued almost indefinitely. I have
set the same loops in motion and stopped them by these solutions as
many as sixteen times in succession.

Magnesium chloride acts in this respect like calcium chloride, and
a similar but slighter action is possessed by strontium chloride.
Magnesium sulphate has a purgative action just as many other sulphates
have. Magnesium citrate also acts in the same way as other citrates.
The action of the magnesium in these cases seems to be subordinate.

In addition to the inhibitory action of calcium and magnesium on
the peristaltic movements of the intestine, these substances also
suppress the secretion of fluid into the intestine. This is shown in
the previous chapter (IV), where tables are given to show the course
of the experiments. According to these experiments, the normal rate
of secretion in an isolated loop was measured. The quantity of fluid
secreted was small, but the application of CaCl_{2} or MgCl_{2} to
the serous surface of the loop stopped the secretion entirely. The
subsequent application of sodium citrate caused it to flow again.

In its counteraction of the effect of saline purgatives, calcium
behaves in the same way. The increased peristalsis or secretion
caused by sodium citrate, sulphate, etc., is entirely suppressed by
the administration of calcium or magnesium chloride. This is not true
to the same extent of those activities produced by barium chloride.
CaCl_{2} as far as I have been able to determine only partially
counteracts the effect of BaCl_{2}. That an antagonism does exist
cannot be doubted, but the violent peristaltic movements brought about
by BaCl_{2} cannot be fully suppressed by CaCl_{2} or MgCl_{2}. As
mentioned above, BaCl_{2} in extremely small doses causes an increased
flow of urine.[55] This can be partially inhibited by CaCl_{2}. With
slightly larger doses of barium, the flow of urine often ceases
abruptly, due probably to the contraction of the musculature of the
urinary passages, or possibly to a contraction of the blood vessels
of the kidney. This condition is relieved by the administration of
CaCl_{2}, that is, the calcium merely counteracts the effect of the
barium on the musculature of the urinary passages or blood vessels,
whichever it may be.

Experiments have recently been made to test the effect of adding
calcium salts to barium chloride and feeding the two mixed with some
edible substance to mice. BaCl_{2} is a common poison to employ for
mice and rats. It was found that the mice eating food containing
barium carbonate alone died, while those eating the mixture of calcium
carbonate and barium carbonate in the food were unharmed.[56]

When loops of the intestine are entirely removed from the body and
placed in sodium chloride solution, active movements begin, as will
be described in detail in a later chapter. These movements continue
40 to 45 minutes or longer if the proper conditions of temperature,
etc., are preserved. If, however, CaCl_{2} be added to this solution
the movements are inhibited. Also loops placed in pure m/6 CaCl_{2}
solution lie perfectly quiet.

A peculiar action of calcium which will be described in detail later
on is shown in the following experiments: A loop of rabbit’s intestine
was removed from the body and placed in a solution of m/6 LiCl. After
moving rhythmically for about 15 seconds the loop came to rest. A
loop similarly placed in m/6 CaCl_{2} solution showed no movements.
In a mixture, however, of 50 c.c. m/6 LiCl + 5 c.c. m/6 CaCl_{2} the
initial movements seen in the pure LiCl solution were absent and the
loop remained quiet for 10-15 minutes. Then sudden sharp constrictions
appear in the loop, followed by violent contractions of the whole loop.
The loop twists and coils upon itself and continues to move in this
extremely active manner for 30-45 minutes or longer. The control loops
in pure LiCl and pure CaCl_{2} remain motionless during all this time.

A similar phenomenon occurs with a mixture of NaCl and CaCl_{2}. In
NaCl, however, the initial movements are much more conspicuous and may
continue for an hour. These are inhibited in the mixture of NaCl and
CaCl_{2}, and after 10-15 minutes movements of an entirely different
character appear, resembling those described for mixtures of LiCl and
CaCl_{2}. Sharp constrictions and violent twistings persist for 30 or
40 minutes.

These peculiar contractions do not occur in mixtures of LiCl and NaCl,
nor in mixtures of CaCl_{2} and MgCl_{2}.

In addition to their action on the intestine, calcium and magnesium
have a very definite action on other organs of the body, more
especially the kidney. It was found[57] that both calcium and magnesium
chlorides inhibit the flow of urine. This is shown in the following
tables taken from the paper referred to.

Rabbit--cannula placed in bladder. No urine flowed in the first or
second periods of 10 minutes before the NaCl solution was injected.

  Time     Salts other than        m/6 NaCl         Urine
            NaCl injected      injected in c.c.    in c.c.

  10:10                               10
  10:15                               10
  10:20                                5             0.5
  10:40                               10             0.8
  11:00                               10             0.5
  11:20                                5             1.0
  11:40                               10             2.8
  12:00                               10             6.0
  12:00   5 c.c. m/6 CaCl_{2}
            intravenously
  12:05   5 c.c. 5m/6 CaCl_{2}
            subcutaneously
  12:20                                5             0.2
  12:40                               10             1.8
   1:00                               10             0.8
   1:00  5 c.c. m/6 sodium citrate
            intravenously
   1:20                               10             2.2
   1:40                                5             3.6

In this case, although the flow of urine was considerably increased
by the injection of NaCl solution, and although the injection was
continued, the introduction of CaCl_{2} caused the flow to almost
cease. This action was quite constant and was obtained in a large
number of experiments. MgCl_{2} has a similar but less powerful effect.
The action of the CaCl_{2} is temporary and wears off after a little
time, as shown in the following table taken from the same paper.
It represents only the latter half of the experiment, the regular
injection of 2 c.c. NaCl solution per minute gradually increasing the
rate of flow as shown, until the quantity of fluid excreted almost
equals that injected.

Rabbit--cannula in bladder--injections intravenous.

  Time     Salts other than        m/6 NaCl         Urine
            NaCl injected      injected in c.c.    in c.c.

   9:25
  11:40                              150            64.5
  11:45                               10             6.6
  11:50                               10             5.6
  11:55                               10             6.2
  12:00                               10             7.4
  12:05                               10             9.5
  12:05   5 c.c. m/6 CaCl_{2}
  12:10                                5             2.2
  12:15                               10             0.8
  12:20                               10             1.2
  12:25                               10             1.6
  12:30                               10             2.8
  12:35                                8             3.0
  12:40                                5             4.5
  12:45                                0             4.8
  12:50                                0             5.1
  12:55                                0             6.2

It was found in another series of experiments[58] that the
haemoglobinuria caused by saponin and by quillain, which is a dried
extract of Quillaja bark, may be inhibited by calcium chloride.
The intravenous injection of 2 c.c. ¹⁄₄% quillain always produced
haemoglobinuria in a rabbit weighing about 1,200 g. If the dilution
of the quillain were made with m/6 CaCl_{2} instead of water, _e.g._,
2 c.c. 1% quillain + 6 c.c. m/6 CaCl_{2} and 2 c.c. of this injected
intravenously, no haemoglobinuria resulted, although the concentration
of the quillain was the same in both cases. The CaCl_{2} does not stop
the excretion of the haemoglobin by the kidneys, for if the saponin
or quillain be given first and the haemoglobinuria established, the
subsequent injection of CaCl_{2} does not stop the excretion of
haemoglobin. This is explained by a large number of experiments in
which it was shown that the haemolysis caused by saponin, quillain,
or digitalin is particularly inhibited by calcium chloride and
magnesium chloride. This can be seen in the following table in which
defibrinated rabbit’s blood is used, and the effects of CaCl_{2} and
MgCl_{2} are compared with that of NaCl.

             1 c.c. blood         1 c.c. blood        1 c.c. blood
   Time    5 c.c. m/6 NaCl     5 c.c. m/6 MgCl_{2}   5 c.c. m/6 CaCl_{2}
         3 drops 0.5% saponin 3 drops 0.5% saponin  3 drops 0.5% saponin
   A.M.
  10:22
  10:24  change of color            no change              no change
  10:27  almost transparent         no change              no change
  10:30  laking almost complete     no change              no change
  10:45  laking complete            no change              no change
   P.M.
   1:00  laking complete        corpuscles settled      same as MgCl_{2}
                                 to bottom; supernatant  mixture
                                 fluid
                                 colored; mixture
                                 quite opaque on
                                 shaking

It is of considerable interest to note that these substances, saponin,
quillain, and digitalin, act not only as haemolytics, but also as
diuretics. This was shown in a number of experiments.[59] As shown in
the following table, the injection of a very small quantity of saponin
produces a distinct increase in the quantity of urine excreted.

            m/6 NaCl injected
  Time        intravenously         Urine
  10:15
  10:20           10 c.c.          2   c.c.
  10:25           20 c.c.          4   c.c.
  10:30           20 c.c.          6 c.c.
  10:35           10 c.c.          7.5 c.c.
  10:40           10 c.c.          8.0 c.c.
  10:45           10 c.c.          8.2 c.c.
  10:50           10 c.c.          7.9 c.c.
  10:56  Injected 2 c.c. ¹⁄₂₀% saponin in m/6 NaCl
  11:00           10 c.c.         10.5 c.c.
  11:05           10 c.c.         11.0 c.c.
  11:10           10 c.c.         11.0 c.c.
  11:15           10 c.c.         11.0 c.c.
  11:16  Injected 1 c.c. ¹⁄₂₀% saponin
  11:20           10 c.c.         12.2 c.c.
  11:25           10 c.c.         13.2 c.c.
  11:30           10 c.c.         12.0 c.c.
  11:35           10 c.c.         12.5 c.c.

It is possible that it is by no means a coincidence that these
substances which are powerful haemolytics act also as diuretics; and
that CaCl_{2} and MgCl_{2}, which inhibit the secretion of urine, also
to some extent inhibit the haemolytic action. It is difficult to say by
what process the haemoglobin is liberated from the red blood corpuscle,
as indeed it is difficult to state definitely how fluid passes from
the blood into the urine. It is sufficient to call attention to the
fact that the liberation of haemoglobin and the flow of urine may be
to some extent controlled by the same conditions. If the haemolytics
such as saponin cause haemolysis by increasing the permeability of
the membranes of the red blood corpuscles, it seems possible that the
diuretic effect of these substances may be due to a similar process
in the kidney. If this be true, changes in permeability must play
an important part in the action of these diuretics. And it is not
impossible that the inhibition of the haemolytic action of saponin,
etc., as well as the inhibition of the flow of urine by CaCl_{2} and
MgCl_{2}, may be due to a decreased permeability of the red blood
corpuscle on the one hand, and of the kidney cells on the other.

With these numerous experiments with calcium and magnesium it is
still impossible to make a general statement as to the nature of
their action. Since the chemical conditions existing in the tissues
of animals and of various parts of animals are largely a matter of
conjecture, we cannot predict how these substances will act; nor can
we say that because calcium, for example, has a certain action in one
animal or on one organ it will necessarily have the same action in
other animals or in other organs.

In the experiments on the rabbit’s intestine, however, calcium and
magnesium have been shown to have an action which can only be described
as inhibitory. In an animal as highly organized as the rabbit, the
intestine is an extremely complex organ; it is not only a muscular
and a glandular organ, but contains a complicated nervous mechanism
peculiar to itself which is entirely inseparable from the other parts.
It is not possible here to mechanically isolate a part which shall
be free from the nervous system as can be done almost completely in
the center of the jellyfish and the apex of the heart. We are dealing
with an entire organ which must be considered as an indicator by
which comparative results may be obtained. So many unknown conditions
exist in such an organ that it is impossible to say what tissue is
acted on primarily, whether the nervous system on the one hand, or
the glandular and muscular tissues on the other. There are, however,
two indicators in the intestine by which the comparative actions of
substances can be studied, namely, the muscular movements, and the
secretion of fluid, both of which by various chemical substances may be
increased or lessened; or, in other words, they may be stimulated or
inhibited. These terms are entirely comparative. The fact that calcium
and magnesium act as inhibitors for both the muscular and secretory
activities of the intestine does not imply that they have a similar
action in other organs or in all animals. It can only be said with
certainty that the chemical conditions under which the intestines of
the rabbit live are fairly constant, so that the addition of calcium or
magnesium in some way constantly inhibits the activity of both muscular
and glandular tissues, and the addition of certain purgative salts
constantly stimulates them to greater activity.


FOOTNOTES:

[49] Journal of Physiology, Vols. 4, 5, 6, 8, 16, 17, and 18, 1883-1895.

[50] Amer. Journ. Physiol., Vol. 2, 1898, p. 47.

[51] Amer. Journ. Physiol., Vol. 2, 1898, p. 82.

[52] Festschrift f. Fick, 1899. Chicago Decennial Publications, 1902,
and Pflüger’s Archiv, Bd. 91, S. 248, 1902. Amer. Journ. Physiol., Vol.
5, 1901.

[53] Amer. Journ. Physiol., Vol. 4, p. 265, 1900; Vol. 8, p. 75, 1902.

[54] Pflüger’s Archiv, Bd. 6, 1872; and Bd. 8, 1874.

[55] MACCALLUM, J. B.: Journal exp. Zoology, No. 1, 1905.

[56] STOVER, F. H.: Bulletin of Bussey Institution, Vol. II, Part IV,
1884.

[57] MACCALLUM, J. B.: Journal Exp. Zoology, Vol. I, No. 1, 1904.

[58] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. II, 1905, p. 93.

[59] MACCALLUM, J. B.: _Loc. cit._




                              CHAPTER VI.

 The Action of Saline Solutions on Loops of Intestine Removed from the
                                 Body.


The fact shown above that local application of saline solutions to the
peritoneal surfaces of the intestine could call forth not only muscular
movements of the intestine, but also an increased secretion, suggested
the possibility of experimenting with loops of intestine entirely
removed from the body. Loops thus isolated are necessarily placed under
new conditions differing entirely from those under which loops normally
connected exist. As mentioned in an early chapter, it was stated by
Claude Bernard that section of the spinal cord below the phrenic causes
active movements to appear in the intestine; and it was later shown by
Pflüger that section of the splanchnic nerves has the same effect, and
stimulation of the peripheral cut ends caused the movements to cease.
It was also noticed by van Braam-Houckgeest that although loops of the
intestine normally connected in the body remained at rest when immersed
in isotonic NaCl solution, active movements appear in the loops when
the splanchnic nerves are cut. Moreau further showed that section of
the mesenteric nerves causes a large increase in the fluid secreted
into the intestine.

I have confirmed these results and have found that loops which are
quiet when the abdomen is opened remain quiet when placed in m/6 NaCl
solution. If, however, loops have become active in any way, through
exposure to the air, or through any stimulation, these movements
continue when the loops are placed in the salt solution. In any case
section of the cervical cord or of the splanchnic nerves, or clamping
of the nerves and bloodvessels supplying the loops, causes a very
marked increase in the peristaltic activity of the loops. In studying
the behavior of isolated loops removed from the body and placed in
various solutions it was therefore necessary to consider the effects
produced by the removal itself.

In describing these experiments, which were made some time ago,[60]
a word may be said as to the methods employed. The rabbits were
anaesthetized with morphine as described before; the abdominal cavity
was opened and the bloodvessels supplying the loop selected were
carefully tied off. Two pairs of ligatures were then placed around the
intestine so that the loop was properly isolated. The intestine was
then cut between each pair of ligatures, and the mesentery divided
between the bloodvessel ligatures and the intestine. In this way the
loop could be taken from the body without injuring it, and without
causing the animal to lose more than a drop or two of blood. The loop
was then emptied by cutting one ligature and allowing the fluid to
drain from that end while it was held up by the ligature of the other
end. The open end was then religatured, and the whole loop suspended in
the solution to be tested. This was arranged so that both ends of the
loop were above the surface of the solution, in order that none of the
solution could by any possibility enter the lumen of the loop through
the ligatured ends. The beakers containing the solutions were kept in
a water bath at 39.5° C. The movements of the loops could in this way
be directly watched, and the amount of fluid secreted in a unit of time
could be easily measured.

If a loop such as has been described above be removed from the
intestine of a rabbit and placed in m/8-m/6 NaCl solution at body
temperature, active movements at once appear. These are regular and
rhythmical, resembling those which set in when the nerves to the
intestine are cut in the uninjured animal. If the loop be allowed
to lie at the bottom of the solution, it will twist and writhe about
in a peculiar worm-like manner. These movements persist in varying
intensity for a considerable time, sometimes as long as an hour,
usually for 40-45 minutes. They disappear gradually. No attempt was
made to obtain a fluid in which the movements could be maintained for
a longer time. These movements are probably merely the continuation of
those always caused by sectioning the nerves to the loop. The m/6 or
m/8 NaCl solution seems to be fairly favorable for their maintenance.
That the loop, however, is not dead when the movements in NaCl cease is
shown by the fact that it can be caused to exhibit active movements by
transferring it to a solution of NaCl containing a small quantity of
BaCl_{2}. It is of course not possible to say that the movements which
appear when the loop is placed in pure NaCl solution are entirely due
to the cutting of the nerves to the loop. It is possible that the NaCl
acts as a direct stimulus and causes the movements to continue.

When a loop is carefully emptied and suspended in a solution of m/8-m/6
NaCl in the way described, it is found that after a considerable time
(20-40 minutes) it is still quite empty. If, on the other hand, an
m/2 solution of NaCl is used the loop is found to contain after 15
to 20 minutes a small but distinct quantity of clear yellowish fluid
resembling the normal intestinal juice. A loop 27 cm. long suspended
in m/2 NaCl for 20 minutes contained 0.6 c.c. fluid. A second loop
30 cm. long in the same solution contained 0.8 c.c. fluid. A control
loop of the same length in m/8 NaCl remained empty. In m/2 NaCl the
movements of the loop are spasmodic and the contractions very strong.
The movements do not usually last more than 5 minutes, although the
loop may be removed from this solution 15 minutes after the movements
have ceased, and may be caused to move again by immersing it in m/8
NaCl containing ¹⁄₂₅ of its volume of m/8 BaCl_{2}. This shows that
the loop is not actually killed by the strong NaCl solution.

A loop suspended in m/6 sodium citrate solution showed active
peristaltic movements, lasting for 20 to 30 minutes. No fluid, however,
collected in this loop. When suspended, however, in m/2 sodium citrate
a measurable quantity of fluid was obtained after 20 minutes. A similar
result was obtained with Na_{2}SO_{4}, active peristalsis, but no
secretion being caused in an m/6 solution. In an m/2 solution, however,
a considerable quantity of fluid collected in the loop.

A loop 28 cm. long suspended in m/8 NaF exhibited active peristaltic
movements which continued for less than 10 minutes. At the end of 20
minutes the loop was found to contain 0.8 c.c. of a clear but slightly
blood-stained fluid.

Loops suspended in m/6 NaCl containing m/6 or m/8 BaCl_{2} in
the proportion of 50 to 1 or 70 to 1 showed very strong muscular
contractions and a well marked secretion of fluid. The muscular
movements were characteristic of barium. Violent local contractions and
firm constrictions of the intestine together with strong peristaltic
movements took place. The loops always contained a distinct and
measurable quantity of fluid after being suspended in this fluid, as
may be seen in the table which follows.

Loops placed in m/6 CaCl_{2} showed no muscular movements whatever,
nor did any fluid gather in the lumen. This is in marked contrast to
the behavior of the loops in the solutions already described. In equal
parts of m/6 NaCl and m/6 CaCl_{2} no movements or secretion took place.

The results of a number of these experiments may be observed in the
following table:--

 =======================================================================
    |       |             |           |Length|    Muscular    |Secretion
    |       |Concentration|           |  of  |    movements   |   of
 No.|  Salt | of Solution |   Time    | loop |  and duration  | fluid
 ---+-------+-------------+-----------+------+----------------+---------
  1 |  NaCl |  m/8        |  40 min.  |30 cm.| Active         | 0.0
    |       |             |           |      |  peristalsis   |
    |       |             |           |      |  40 min.       |
    |       |             |           |      |                |
  2 |  ”    |   ”         |  20  ”    |23  ” | Active         | 0.0
    |       |             |           |      |  peristalsis   |
    |       |             |           |      |  40 min.       |
    |       |             |           |      | Strong         |
  3 |  ”    |  m/2        |  20  ”    |30  ” |  contractions  | 0.8 c.c.
    |       |             |           |      |  5 min.        | clear
    |       |             |           |      |                | yellow
    |       |             |           |      |                | fluid.
    |       |             |           |      | Strong         |
  4 |  ”    |   ”         |  20  ”    |30  ” |  contractions  | 0.6 c.c.
    |       |             |           |      |  5 min.        | clear
    |       |             |           |      |                | yellow
    |       |             |           |      |                | fluid.
 ---+-------+-------------+-----------+------+----------------+---------
  5 |  Sod. |  m/8        |  20  ”    |20  ” | Active         | 0.0
    |  Cit. |             |           |      | peristalsis    |
    |       |             |           |      |  20 min.       |
    |       |             |           |      |                |
  6 |  ”    |  m/2        |  20  ”    |32  ” | Violent        | 0.4 c.c.
    |       |             |           |      |  contractions  | clear
    |       |             |           |      |  2-3 min.      | yellow
    |       |             |           |      |                | fluid.
 ---+-------+-------------+-----------+------+----------------+---------
  7 |Na₂SO₄ |  m/8        |  20  ”    |33  ” | Active         | 0.0
    |       |             |           |      | peristalsis    |
    |       |             |           |      |                |
  8 |  ”    |  m/2        |  20  ”    |30  ” | Strong         | 1.5 c.c.
    |       |             |           |      | contractions of| clear
    |       |             |           |      | short duration.| yellow
    |       |             |           |      |                | fluid.
 ---+-------+-------------+-----------+------+----------------+---------
  9 | NaF   |  m/8        |  20  ”    |28  ” |  Strong        | 0.8 c.c.
    |       |             |           |      |   contractions | slightly
    |       |             |           |      |   10 min.      | bloody.
 ---+-------+-------------+-----------+------+----------------+---------
 10 |{NaCl  |m/8-70 c.c.} |  20  ”    |25  ” |Active mov’m’ts.| 0.6 c.c.
    |{BaCl₂ |m/8-1 c.c. } |           |      |                | clear
    |       |             |           |      |                | yellow
    |       |             |           |      |                | fluid.
    |       |             |           |      |                |
 11 |  ”    |   ”         |  20  ”    |46  ” |Active mov’m’ts.| 0.8
    |       |             |           |      |                | c.c.
    |       |             |           |      |                |
 12 |  ”    |   ”         |  20  ”    |60  ” |Active mov’m’ts.| 1.2
    |       |             |           |      |                | c.c.
    |       |             |           |      |                |
 13 |  ”    |   ”         |  20  ”    |31  ” |Active mov’m’ts.| 1.2
    |       |             |           |      |                | c.c.
    |       |             |           |      |                |
 14 |{NaCl  |m/8-50 c.c.} |1st 20 min.|63  ” |Active mov’m’ts. | 1.6
    |       |             |           |      |                | c.c.}
    |{BaCl₂ |m/8-1 c.c. } |2nd 20  ”  |      |                | 0.2
    |       |             |           |      |                | c.c.}
    |       |             |           |      |                |
 15 | BaCl₂ |m/8-50 c.c.} |1st 20 min.|32  ” | Violent        | 2.7
    |       |             |           |      | contractions.  | c.c.}
    |       |             |2nd 20 min.|      |                | 0.2
    |       |             |           |      |                | c.c.}
    |       |             |           |      |                |
 16 |{NaCl  |m/8-30 c.c.} |  20 min.  |23  ” | Violent        | 0.9
    |{BaCl₂ |m/8-30 c.c.} |           |      | contractions.  | c.c.
    |       |             |           |      |                |
 17 | CaCl₂ |    m/8      |  20  ”    |20  ” |  None          | None
    |       |             |           |      |                |
 18 |  ”    |     ”       |  20  ”    |15  ” |   ”            |  ”
    |       |             |           |      |                |
 19 |{CaCl₂ |m/8-50 c.c.} |  20  ”    |10  ” |   ”            |  ”
    |{NaCl  |m/8-50 c.c.} |           |      |                |
    |       |             |           |      |                |
 20 |{CaCl₂ |m/2-50 c.c.} |  20  ”    |15  ” |Slight movements|  ”
    |{NaCl  |m/2-50 c.c.} |           |      | not peristaltic|
    |       |             |           |      | in character.  |
    |       |             |           |      |                |
 21 |{CaCl₂ |m/1-50 c.c.} |  20  ”    |15  ” |Slight movements| Slight
    |{NaCl  |m/1-50 c.c.} |           |      | not peristaltic| trace.
    |       |             |           |      | in character.  |
    |       |             |           |      |                |
 22 |{NaCl  |m/8-30 c.c.} |  20  ”    |35  ” | Irregular      | None.
    |{BaCl₂ |m/8-1 c.c. } |           |      | contractions   |
    |{CaCl₂ |m/8-30 c.c.} |           |      | not strong     |
    |       |             |           |      |                |
 23 |{NaCl  |m/8-30 c.c.} |  20  ”    |30  ” | Irregular      | 0.2
    |{BaCl₂ |m/8-1 c.c. } |           |      | contractions,  | c.c.
    |{CaCl₂ |m/8-30 c.c.} |           |      | not strong     |
    |       |             |           |      |                |
 24 |{BaCl₂ |m/8-1 c.c. } |  20  ”    |30  ” | Irregular      | 0.2
    |{CaCl₂ |m/8-50 c.c.} |           |      | contractions.  | c.c.
 ---+-------+-------------+-----------+------+----------------+---------

It is interesting to note again here that the secretion into these
loops is almost uniformly inhibited by the presence of calcium. When
barium is also present in the solution this inhibition is only partial.
The action of barium is never entirely counteracted by calcium chloride.

The experiments further show that the saline purgatives act on the
intestine not only when it has its normal position and connections
with the rest of the body, but also when it is entirely isolated. This
eliminates in the first place the possibility of the solutions acting
entirely through the central nervous system. It is possible that the
salts have some influence on the central nervous system, but from these
experiments it seems probable that their main action is either on
the glandular and muscular tissues themselves, or on the plexuses of
Auerbach and Meissner in the intestinal walls.

As I have already shown, the action of a saline purgative on the
intestine consists of two parts, the increase of the peristaltic
activity and the increase of the amount of fluid secreted into the
lumen; or, in other words, the action on the muscle and the action on
the glandular tissue. In the experiments just described it is clear
that these two separate actions exist side by side. For example, m/8
solutions of sodium chloride, citrate, or sulphate cause well marked
peristaltic movements or allow these to continue, while no secretion
of fluid takes place. Stronger solutions of these salts, on the other
hand, such as m/2 produce a distinct secretion. Thus a concentration
of a salt which is sufficient to produce muscular activity may not
be sufficient to affect the glandular tissues. One is tempted to
conclude that in the intestine it requires a stronger stimulus to
produce secretory activity than it does to cause muscular movements.
It is possible that this is true, but the anatomical relations also
must be taken into consideration. The muscle coats lie immediately
under the thin peritoneal layer through which the salts are absorbed;
and it seems probable that in the experiments described the solutions
reached the muscle more easily and rapidly than they could the
glandular tissue which is situated on the other side of the muscular
and submucous layers. Further, it must be noticed that the movements
seen in m/8 NaCl may be merely the continuation of those caused by
separation of the loop from the central nervous system.

The amount of fluid which may be secreted by a loop of intestine
isolated from the body is limited by the absence of the blood supply.
The loop, as shown above, secretes a certain amount of fluid in the
first 10 or 20 minutes. If it is then emptied, usually no more fluid
appears. The quantity secreted depends on the amount of fluid contained
in the intestinal walls at the time of its removal from the body. No
fluid passes from the solution in which the loop is suspended into the
lumen of the loop; no current is established through the walls from the
outside inwards. It seems possible to supply the stimulus for secretion
in the solution in which the loop is suspended; but it is not possible
in this way to renew the fluid which the glands have secreted into the
lumen. This can apparently be done only through the blood vessels.


FOOTNOTES:

[60] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. I, 1904, p. 115.




                             CHAPTER VII.

    The Action on the Intestine of Solutions Containing Two Salts.


As stated above, it was shown by Claude Bernard and by Pflüger that
section of the spinal cord below the phrenic nerve, or section of
the splanchnic nerves, causes a marked increase in the intestinal
movements, and also an increase in the amount of fluid secreted
(Moreau). These movements continue in loops isolated and removed from
the body and placed in m/6 NaCl, LiCl, Na_{2}SO_{4}, sodium citrate,
etc., for varying periods of time. They continue far longer in NaCl
than in any other solution. Calcium chloride inhibits these movements,
as is the case also with magnesium chloride. It was found,[61] however,
in making these experiments with isolated loops removed from the body,
that with certain mixtures of NaCl or LiCl with CaCl_{2} or MgCl_{2},
movements began after 20 or 25 minutes of a character differing
entirely from the movements seen in pure NaCl. An idea of this
phenomenon may be gained from the following description of experiments.

A word may be first said with regard to the methods used in these
experiments. In rabbits anaesthetized as usual, the abdomen was opened
and a loop 30-40 cm. in length isolated by ligatures. By means of a
needle and thread the blood vessels supplying the loop were carefully
tied and the loop rapidly excised. It was then cut into a number of
pieces, usually four, which were transferred with as little handling
as possible to the beakers containing the solutions to be tested.
These beakers were kept in a water bath at 39.5° C. It is desirable in
these experiments to use loops which contain no faeces, since unknown
substances in the faeces might go into solution and disguise the action
of the salt being tested. For this reason the upper part of the small
intestine was principally used since in the rabbit it is usually empty
or can be readily emptied. In each set of experiments the loops must
all come from the same rabbit, for there exist considerable differences
in irritability in different animals. On account of these differences
it is necessary to have control experiments in the case of each rabbit.
Loops also which have been unduly exposed to the air cannot be used.
It is of great importance to keep the solutions at a constant body
temperature.

_(a) LiCl and CaCl_{2}._ A loop of intestine removed from the body and
placed in an m/6 LiCl solution at body temperature usually exhibits
only slight movements, which soon cease. This seems to vary somewhat
with different rabbits. In some cases the loop shows no movements at
all, while in other instances it moves regularly for half a minute
and then comes to rest in the solution. These movements are quiet and
regular and resemble those described in loops immersed in m/6 NaCl
solution. When a loop has ceased to move it does not become active
again. In exceptional cases these movements may last 5-10 minutes, but
rarely longer. The LiCl solution seems less favorable for the long
duration of the movements than the NaCl.

A loop similarly immersed in m/6 CaCl_{2} solution at body temperature
remains in the great majority of cases quite motionless from the first.
In some instances slight movements appear immediately after it is
placed in the solution, but these soon disappear. After 25-40 minutes
it is not uncommon to see the loop slowly straighten out, and at the
end of this time the length of the loop is much less than it was at
first. This seems to be due to a slow contraction of the longitudinal
muscle layer, so slow that no movement can be observed. A difference
is seen also in the shape of the loops placed in LiCl and in CaCl_{2}.
The former after it comes to rest is practically its original length
and is coiled up in a circle; the latter is about half its original
length and is almost straight.

A loop similar to the above placed in 50 c.c. m/6 LiCl + 5 c.c. m/6
CaCl_{2} behaves in a manner entirely different from loops from the
same animal placed in either LiCl or CaCl_{2} alone. On being first
immersed in the mixture it exhibits practically no movements. Even in
cases where the control loop is active at first the corresponding loop
in the mixture of LiCl and CaCl_{2} shows no movements. It remains
perfectly quiet for 10-15 minutes. Then sharp constrictions appear
here and there in the loop. These are followed a second or two later
by violent contractions which cause the loop to coil upon itself in a
most active manner. These contractions somewhat resemble those caused
by BaCl_{2} in the intact intestine. They follow one another rapidly
so that the loop is turned and twisted tightly upon itself. This
extreme activity persists for 30-45 minutes, sometimes for an hour,
while during all this time the control loops in LiCl and in CaCl_{2}
are entirely motionless. These movements are not at all of the same
character as those which may appear at the beginning in pure LiCl
solution, and could not be considered as these same movements delayed.
Such an experiment is outlined in the following table:--

    Time.
    Loops                        50 c.c. m/6 LiCl          50 c.c.
   placed in   50 c.c. m/6 LiCl    + 5 c.c. m/6          m/6 CaCl_{2}
  solutions at                       CaCl_{2}

    10:05      no movements     no movements             no movements
    10:10      no movements     no movements             no movements
    10:15      no movements     no movements             no movements
    10:19      no movements     violent movements begin  no movements
    10:25      no movements     very active movements    no movements
    10:30      no movements     very active movements    no movements
    10:45      no movements     very active movements    no movements
    10:50      no movements     movement less active     no movements
    11:00      no movements     movement very slight     no movements
    11:15      no movements     movement almost stopped  no movements
    11:20      no movements     no movements             no movements

By varying the proportions of LiCl and CaCl_{2} the results may be
somewhat changed. The characteristic contractions may be obtained with
as small a quantity of CaCl_{2} as in a mixture of 50 c.c. m/6 LiCl +
¹⁄₂ c.c. m/6 CaCl_{2}. The movements, however, last only 5-10 minutes
and are less active than in a mixture of 50 LiCl + 5 CaCl_{2}. This
latter mixture seems to be perhaps the most favorable, although almost
equally powerful contractions are obtained with mixtures containing
as much as 10 c.c. CaCl_{2} to 50 c.c. LiCl. When more CaCl_{2} than
this is added the movements usually appear later and last a much
shorter time. With equal parts of LiCl and CaCl_{2} they cease in 15
to 20 minutes, while in a mixture of 5 c.c. LiCl + 50 c.c. CaCl_{2}
the movements appear late and last only 4 or 5 minutes. The loops
in mixtures with relatively much CaCl_{2} come to rest in the shape
characteristic of loops in pure CaCl_{2}. They become shortened and
are found to be straightened out at the end of the experiment. Where
relatively much LiCl is present the loops remain almost their original
length and are usually coiled. This is shown in the following table:--

                         50 c.c. Li Cl   50 c.c. CaCl_{2}
 Time   50 c.c. LiCl        +                +          50 c.c. CaCl_{2}
                         5 c.c. CaCl_{2} 5 c.c. LiCl

 11:14  Length of loop  Length of loop  Length of loop    Length of loop
          10 cm.            10 cm.          10 cm.             10 cm.
 11:14  no movements    no movements    no movements       no movements
 11:20  no movements    very active     no movements       no movements
                          movements
 11:35  no movements    very active     movements          no movements
                          movements       begin
 11:40  no movements    very active     Movements          no movements
                          movements       slow
 11:50  no movements    very active     no movements       no movements
                          movements
 12:00  no movements    very active     no movements       no movements
                          movements
 12:05  no movements    no movements    no movements       no movements
 12:10  Length about    Length about    Length about       Length about
          8 cm.             8 cm.           4 cm.              4 cm.

These muscular contractions which appear in mixtures of LiCl and
CaCl_{2}, and do not appear in either LiCl or in CaCl_{2} alone, are
not the continuation of movements caused by separating the loop from
the central nervous system. These latter movements which are sometimes
seen for a short time following the immersion of the loop in pure LiCl
solution are inhibited by CaCl_{2}. Further, the movements which come
on later in mixtures of LiCl and CaCl_{2} are of entirely different
character, being convulsive and violent and many times more powerful
than any movements seen in pure LiCl. If they were the movements seen
in pure LiCl, only delayed by the CaCl_{2}, they should be more active
in solutions containing the least CaCl_{2}. This is not the case,
since in a mixture of 50 c.c. LiCl + ¹⁄₂ c.c. CaCl_{2} they are by
no means so active as in 50 c.c. LiCl + 5 c.c. CaCl_{2}. A further
experiment shows this still more clearly. A loop placed in 50 c.c. m/6
LiCl was allowed to come to rest, and was left in the solution for 10
minutes. No movements whatever were to be seen at this time. There were
then added 5 c.c. m/6 CaCl_{2} to the LiCl solution containing the
motionless loop. Within one minute the loop became violently active in
the characteristic way described above. This activity continued for
nearly an hour.

In attempting to explain this phenomenon one is tempted to take Loeb’s
suggestion as to the action of calcium in Gonionemus, namely, that
it counteracts the poisonous effect of the sodium chloride. If the
LiCl solution were toxic, however, it is difficult to imagine that
the loop could be restored suddenly to activity as described above by
the addition of a small quantity of CaCl_{2}, after it had lain in
pure LiCl solution for 10 minutes. It is also difficult to consider
calcium as a stimulating agent in this case, since, as shown above, in
all other instances in the intestine it has the opposite action. Also
calcium chloride alone in no concentration causes this phenomenon. The
action of CaCl_{2} in this instance is suggestive of the action of
a catalyser, the addition of which enormously hastens some chemical
reaction. It is possible that the muscular activity in this case
depends on a chemical reaction which is brought about neither by LiCl
nor by CaCl_{2}, but by a combination of these two or perhaps by an
intermediate product.

Whatever may be the explanation of these phenomena, the fact remains,
and is easy of demonstration, that an effect is produced on isolated
loops of intestine by a combination of LiCl and CaCl_{2} which is
entirely different from what can be produced by either LiCl or CaCl_{2}
alone.

(_b_) _NaCl_ + _CaCl_{2}_. The phenomena described above as occurring
when isolated loops of intestine are immersed in mixtures of LiCl and
CaCl_{2} can be produced also in mixtures of NaCl and CaCl_{2}. The
behavior of loops placed in pure CaCl_{2} and in pure NaCl has been
described. In the former the loop remains motionless; in the latter
regular rhythmical movements continue for 40 minutes or more.

When, however, a loop is placed in 50 c.c. m/6 NaCl + 10 c.c. m/6
CaCl_{2} there are no movements whatever to be seen at first. The
loops remains quiet for about 10 minutes. The movements which are seen
from the beginning in the control loop in pure NaCl solution have
apparently been inhibited by the CaCl_{2} present in the mixture.
After 10 minutes, however, the loop gradually becomes very active, and
violent contractions appear which are similar to those described as
taking place in mixtures of LiCl and CaCl_{2}. The loop becomes much
more active than the control loop in pure NaCl. The onset in the LiCl
mixture is more sudden, but otherwise the phenomenon is practically the
same. The movements in NaCl + CaCl_{2} persist for 30 or 40 minutes,
sometimes for an hour. When the concentration of the CaCl_{2} in the
mixture is relatively great this effect is not obtained. This is shown
in the following table:--

  Time    50 c.c. NaCl    50 c.c. NaCl       50 c.c. NaCl
                          + 5 c.c. CaCl_{2}  + 10 c.c. CaCl_{2}

  10:35  quite active    no movements       no movements
  10:40  quite active    no movements       no movements
  10:45  quite active    slight movements   slight movements
  10:50  less active     slight movements   slight movements
  10:55  still active    very active        very active
  11:00  still active    extremely active   extremely active
  11:15  still active    extremely active   extremely active
  11:30  almost stopped  extremely active   extremely active
  11:45  no movements    movements quieter  movements quieter
  11:50  no movements    no movements       no movements


  Time    50 c.c. NaCl       50 c.c. NaCl       50 c.c. CaCl_{2}
          + 20 c.c. CaCl_{2} + 40 c.c. CaCl_{2}

  10:35  no movements       no movements       no movements
  10:40  no movements       no movements       no movements
  10:45  no movements       no movements       no movements
  10:50  no movements       no movements       no movements
  10:55  no movements       no movements       no movements
  11:00  no movements       no movements       no movements
  11:15  no movements       no movements       no movements
  11:30  no movements       no movements       no movements
  11:45  no movements       no movements       no movements
  11:50  no movements       no movements       no movements
Thus here also, as in the case of LiCl and CaCl_{2}, there are produced
effects in mixtures of NaCl and CaCl_{2} which cannot be brought about
by either salt alone. The presence of CaCl_{2} seems to inhibit the
movements which are first present in a loop placed in NaCl solution.
When added in small quantities, _e.g._, not more than 10 c.c. m/6
CaCl_{2} to 50 c.c. m/6 NaCl, it produces after an interval of 10-15
minutes very violent movements such as are never seen in pure NaCl
solution nor in pure CaCl_{2}. When, however, it is added in greater
proportion than this, e.g., 20 or more c.c. CaCl_{2} to 50 c.c. NaCl,
all movements are stopped. The explanation of this is no more clear
than the similar occurrence in mixtures of LiCl and CaCl_{2}.

If a loop be placed in a mixture of LiCl and NaCl in equal parts,
movements appear such as are seen in pure NaCl, but do not persist
for so long a time. In the mixture of these two salts no such result
is obtained as has been described in mixtures of LiCl and CaCl_{2} or
of NaCl and CaCl_{2}. Mixtures of CaCl_{2} and MgCl_{2} also produce
no such movements. In these few salts it seems to be a mixture of
chlorides of a monovalent with a bivalent metal which produces the
extreme activity of the loop, while mixtures of chlorides of two
monovalent metals or of two bivalent metals do not bring this about.


FOOTNOTES:

[61] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. II, 1905, p. 47.




                             CHAPTER VIII.

     The Effect on the Intestine of Intravenous Saline Infusions.


It has been frequently observed that a quantity of fluid enters the
intestine during the intravenous injection of normal salt solution.
According to Dastre and Loye,[62] the fluid injected into the veins
is largely eliminated by the kidneys, although these organs may be
assisted in this function by the salivary glands and intestine. These
authors have found fluid to be present in the intestine of rabbits as
well as in the pleural and peritoneal cavities after the injection
of large quantities of salt solution. They state that in such an
intravenous injection diarrhœa often results which may be so pronounced
that a clear fluid emerges from the rectum. Knoll[63] also mentions the
production of diarrhœa by the injection of large quantities of NaCl
solution.

Magnus[64] in his work on the production of oedema of the skin by
intravenous infusions of salt solutions shows in his tables that a
certain amount of fluid is eliminated by the intestines after the
kidneys have been removed. A rabbit with both kidneys removed was
infused with 1,500 c.c. normal salt solution; 200 g. were eliminated
by the intestine. In a second rabbit 1,010 c.c. of fluid were injected
into the veins and 60 g. were eliminated by the intestine. In a dog
1,760 c.c. were injected and 160 g. eliminated by the intestine.

I have made a number of experiments[65] in which the amount of fluid
passing into the intestine during the intravenous injection of large
quantities of NaCl solution was determined not only when the kidneys
were removed from the circulation, but also when they were active. As
shown by the following experiments, the fluid secreted by the intestine
increases rapidly when m/8 or m/6 NaCl solution is injected into
the blood. Without such an injection or other stimulus very little
intestinal juice can be gathered in a time as short as that occupied by
the experiments. In a rabbit’s small intestine there is usually found
between 5 and 10 c.c. fluid, often much less.

Exp. 1. Rabbit. The bloodvessels to the kidneys were tied off and two
cannulæ were put into the intestine, one 35 cm. from the pylorus and
the other in the lower part of the ileum. Each loop was isolated by
ligatures. The upper one was about 30 cm. long and the lower one 42
cm. The upper loop in the beginning contained 5 c.c. fluid, which were
removed. The lower loop was empty. During the first hour 100 c.c. m/8
NaCl were forced into the blood and 5.2 c.c. fluid appeared in the
upper loop and nothing in the lower loop. During the second hour 240
c.c. NaCl solution were injected and 5.4 c.c. fluid appeared in the
upper loop and 13.6 c.c. in the lower loop. During the third hour 160
c.c. NaCl solution were introduced; 6.6 c.c. fluid appeared in the
upper loop and 15.5 c.c. in the lower. The infusion was then stopped
and 26 c.c. were found in the part of the small intestine not included
in the loops. The total amount thus secreted by the intestine in three
hours was 72.3 c.c. This is 14.46% of the quantity injected.

Exp. 2. In another rabbit with kidneys removed, 470 c.c. NaCl solution
were injected during three hours, and 78 c.c. fluid obtained from the
intestine, which is about 16.6% of the quantity injected.

Exp. 3. In a rabbit in which the kidneys were left intact, 547 c.c. m/6
NaCl solution were injected into the blood. 49.5 c.c. were secreted in
3 hours and 30 minutes by the intestine. This is about 9% of the total
quantity of fluid. The quantity of fluid secreted into the loop in the
first half hour was 1.8 c.c.; in the third half hour, 2.9 c.c.; in the
fifth half hour, 6.6 c.c.

Exp. 4. In a second rabbit in which the kidneys were untouched, the
quantity of m/8 NaCl solution introduced was 390 c.c.; about 40 c.c.
of fluid were obtained during three hours from the intestine. This is
10.25% of the amount injected. In the first hour 5 c.c. were secreted
into the loop; in the second hour 7 c.c.; and in the third hour 11.1
c.c. In the rest of the small intestine 17 c.c. were found.

It is clear from these experiments that a considerable proportion of
the fluid injected in this way is eliminated by the intestine. The
quantity is somewhat greater if the kidneys are extirpated. There is,
however, a limit to the amount that can be excreted by the intestine,
and never, as in the case of the kidney, does the amount excreted
approximate the amount injected. The action of such infusions on the
intestine is nevertheless quite similar to that on the kidneys, and
in many other ways the intestine may be regarded as an excretory
organ which can to some extent take on the functions of the kidney.
The intestinal juice contains many substances contained by the urine.
Among the more conspicuous of these is urea, which was shown by Claude
Bernard[66] to be excreted into the intestine as well as the stomach.
He found that it is readily broken up in the intestinal juice, so that
in many cases only salts of ammonia remain.

Pregl[67] demonstrated the presence of urea in the intestinal juice
of the sheep. He found its concentration there to be 0.248%. In the
intestinal juice of rabbits I[68] have found that small quantities of
urea exist both before and after extirpation of the kidneys. It is
present not only in the normal intestinal juice, but also in the fluid
obtained from the intestine after the infusion of large quantities of
m/6 NaCl. Weintrand[69] has demonstrated uric acid in the intestinal
juice.

_Secretion of sugar into the intestine._ Another instance of the way
in which the intestine can to some extent take up the function of the
kidney is shown by the secretion of sugar by the gut following the
injection of large quantities of normal salt solution. It was shown by
Bock and Hoffmann[70] that the injection of 1% NaCl solution into the
circulation of a rabbit caused transient glycosuria. Large quantities
of the solution were injected at the rate of 25-30 c.c. each 5 minutes,
and the glycosuria appeared in from 20 minutes to 1 hour and 30 minutes
after the beginning of the infusion. After a number of hours (6-7) the
glycosuria diminished in their experiments and finally disappeared,
although the infusion of salt and the flow of urine continued. They
found that the entire quantity of sugar eliminated was in one case
1.632 g., and in another case 2.04 g. The percentage of sugar in the
urine reached 0.136 and 0.219 respectively in the two experiments.
These facts were confirmed by Külz,[71] who found also that section
of the splanchnics prevented the glycosuria. The experiments lately
published by M. H. Fischer[72] show that the glycosuria is caused not
only by NaCl, but by certain of the salts which were shown by Loeb[73]
to produce muscular twitchings. He further showed that calcium has the
power of suppressing the glycosuria.

This secretion of sugar by the kidneys following intravenous infusions,
together with the facts shown above that fluid is eliminated to some
extent by the intestine in the absence of the kidneys, led me to
inquire whether the intestine also secretes sugar when the kidneys have
been extirpated and a large amount of NaCl solution is injected. A
number of experiments were made to determine this. I have found[74] in
brief that with the infusion of large quantities of m/6 NaCl solution
into the circulation sugar is abundantly secreted into the intestine.
This takes place not only when the kidneys are removed, but also when
they are intact, and are also eliminating sugar. This may be seen in
the following tables:--

Rabbit--Blood vessels of kidney ligatured; cannula in upper part of
small intestine, with loop 35 cm. tied off. Loop emptied; contents 5
c.c., which contained no sugar.

             NaCl m/6         Intestinal      Sugar examination of
  Time        injected          juice           intestinal juice

  10:00    Infusion begun    Loop emptied,     No sugar
                                5 c.c.
  10:30        20 c.c.          3 c.c.         No sugar
  11:00        40 c.c.          3 c.c.         No sugar
  11:30        20 c.c.          4 c.c.         No sugar
  12:00       120 c.c.          6 c.c.         Trace of sugar
  12:30       200 c.c.         12 c.c.         Sugar abundant
   1:00         --c.c.         28 c.c.         Sugar abundant
              --------
              400 c.c.

Here the sugar appeared in the intestinal juice after about 200 c.c.
NaCl solution had been injected. The injection was made in each case
into the vein of the ear by means of a pressure bottle connected with
the water tap. The pressure bottle was in turn connected with a bottle
holding the solution, which was thus forced out at a constant rate
through a long rubber tube immersed in water at 40° C. A hypodermic
needle was fastened in the end of this tube and inserted into the
marginal vein of the rabbit’s ear. In this way the quantity of fluid
injected could be accurately measured and controlled. The salt solution
after passing through the long tube reached the ear at approximately
body temperature. It is of the greatest importance to protect the
intestinal loops in every way possible from loss of heat or from drying.

In the above experiment the _intestinal glycosuria_, if such a term may
be applied to this phenomenon, appears under circumstances which are
exactly the same as those necessary for the production of sugar in the
urine by saline infusions. A further example of this is shown in the
following experiment:--

Rabbit--Blood vessels of both kidneys ligatured. Intestinal loop
including duodenum 32 cm. long. In the loop were found 3 c.c. fluid
which contained no sugar.

             NaCl m/6      Intestinal    Sugar examination of
  Time        injected       juice         intestinal juice

   9:45    Infusion begun Loop emptied,  No sugar
                             3   c.c.
  10:15        10 c.c.       3   c.c.    No sugar
  10:45        70 c.c.       3   c.c.    No sugar
  11:15        75 c.c.       3.2 c.c.    No sugar
  11:45        85 c.c.       5   c.c.    Sugar abundant } 0.202%
                                                        } 0.222%
  12:15        80 c.c.       9.5 c.c.    Sugar abundant 0.25%
  12:45       150 c.c.      21   c.c.    Sugar abundant
              --------
              470 c.c.

Here the sugar appeared after the infusion of about 240 c.c. NaCl
solution. The experiment was not carried on to see how long the sugar
would continue to be present in the intestinal juice. The animal
was killed, and it was found that the remaining loops of the small
intestine held 32 c.c. of fluid which contained sugar. The stomach
contents included about 40 c.c. fluid which also contained sugar. Of
the 470 c.c. of fluid injected, 78.7 c.c. were eliminated by the small
intestine and 40 by the stomach. The alimentary canal, then, exclusive
of the large intestine, eliminated about 118 c.c. of the fluid
introduced, which is approximately 25%.

Quantitative estimations of the sugar in the intestinal juice in
this case were made. The amount varied between 0.2 and 0.3%. I have
not attempted to ascertain the total quantity of sugar which may be
obtained from the intestinal juice by continued infusion of salt
solution. In the case of the urine, Bock and Hoffmann made such
determinations and found that the kidney eliminated in one case 1.632
g. and in another case 2.04 g. sugar. M. H. Fischer found that the
concentration of sugar in the urine of a rabbit rarely exceeds 0.25%
after infusion of m/6 NaCl.

Thus the intestine eliminates sugar in a way that entirely resembles
its elimination by the kidneys. The sugar appears in the blood after
the infusion of a certain amount of the salt solution and is excreted
by the kidney. If the kidneys are removed, it is excreted by the
intestine. But even when the kidneys are intact there is a certain
amount of sugar excreted by the intestine, just as a part of the fluid
injected is eliminated by the intestine when the kidneys are still
active. As shown in the following experiment, the sugar appears both in
the intestinal juice and in the urine. The quantity of sugar, however,
is greater in the urine than in the intestinal juice. In the urine it
was found to be about 0.2%, in the intestinal juice considerably less.
The quantity of urine also is greater than the quantity of intestinal
juice. Therefore the greater proportion of the sugar is excreted by the
kidneys.

Rabbit--Cannula placed in bladder. Kidneys intact. Cannula in loop of
upper part of small intestine 35 cm. long. Loop contained 4.2 c.c.
fluid; no sugar.

                       Intestinal juice.           Urine.
         NaCl m/6  /---------------------\/----------------------\
  Time.  injected.   Quantity.    Sugar     Quantity.     Sugar
                               examination.            examination.
   9:45  Infusion   Loop emp’d,  No sugar.   Bladder       No sugar.
          begun.      4.2 c.c.              emptied, 5 c.c.
  10:15    5 c.c.     1.8 c.c.    ” ”           0.0
  10:45   50 ”        2.2 ”       ” ”           0.0
  11:15   80 ”        2.9 ”       ” ”           4.0 c.c.    No sugar.
  11:45   92 ”        3.8 ”       ” ”           15.0      Sugar present.
  12:15  120 ”        6.6 ”    Sugar present.   38.0      Much sugar.
  12:45  150 ”        7.8 ”       ” ”           40.0         ”  ”
         -----
         497 ”

It is interesting to note in connection with these experiments the
secretion of sugar into the stomach which followed the intravenous
infusion of NaCl solution. Ordinarily in the normal rabbit only a very
small quantity of fluid can be obtained from the stomach. This was
not found in my experiments to contain sugar. In one case after the
infusion of 470 c.c. NaCl solution the stomach contained about 40 c.c.
of fluid. In a second instance 32.8 c.c. of fluid were secreted by the
stomach during 2 hours and 30 minutes, during which time 390 c.c. NaCl
solution were injected. In both these experiments sugar, which was not
present in the beginning, appeared in considerable quantities after the
infusion had continued for a little time. Thus the stomach excretes
sugar under circumstances similar to those under which it is excreted
by the intestine. Claude Bernard[75] describes the presence of sugar in
the gastric contents of diabetic patients. He quotes McGregor as having
made the observation by causing patients to vomit. On examination of
the gastric contents sugar was demonstrated. It seems possible that in
this case the food might have contained a reducing substance.

Thus a study of the effect of saline infusions on the intestine leads
us to the idea of the alimentary canal as in some sense a subsidiary
excretory organ. In addition to its other better known functions, the
intestine can to some extent take on some of the functions of the
kidney. As shown above, it not only tends to eliminate an excess of
fluid forced into the circulation, but also excretes urea and uric
acid. Further, under circumstances which cause glycosuria, sugar is
also excreted by the intestine.


FOOTNOTES:

[62] Arch. de physiol. norm. et path., 4 e série, 2, 1888, p. 93; 5 e
série, 1, 1889, p. 253.

[63] Arch. für exp. Path. u. Pharm., Bd. XXXVI, S. 293, 1895.

[64] Arch. für exp. Path. u. Pharm., Bd. XLII, S. 250, 1899.

[65] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. I, 1904, p. 125.

[66] Leçons sur les propriétés physiologiques et les altérations
pathologiques des liquides de l’organisme, II Tome, Paris, 1859.
Deuxième Leçon.

[67] Archiv für die gesammte Physiologie, Bd. 61, 1895, p. 378.

[68] _Loc. cit._

[69] Chemische Centralblatt, Leipzig, Bd. II, 1895, S. 310.

[70] BOCK and HOFFMANN: Arch. für Anat., Physiol. und wissenschaftl.
Med. (Reichert und DuBois-Reymond), p. 550, 1871.

[71] KÜLZ: C. Eckhard’s Beiträge, Bd. 6, S. 117, 1872. (Quoted by
Pflüger, Arch. für die gesammte Physiologie, Bd. 96, 1903, S. 313.)

[72] M. H. FISCHER: University of California Publications, Physiology,
Vol. I, pp. 77 and 87, 1904.

[73] LOEB, J.: Festschrift für Fick, 1899; Pflüger’s Archiv, 1902, XCI,
p. 248.

[74] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. I, 1904, p. 125.

[75] Leçons sur les propriétés physiologiques des liquides de
l’organisme, T. II, 1859, p. 74.




                              CHAPTER IX.

               Mode of Action of the Saline Cathartics.


Since the discovery of sodium sulphate by Glauber in the middle of the
seventeenth century, and the preparation of the double tartrate of
sodium and potassium at Rochelle some fifteen years later, the saline
cathartics have been in constant use among physicians. Attempts have
been made also from the first to explain in some way their mode of
action; but it was not until the discovery of the osmotic property
of salts that any explanation which seemed satisfactory was made.
Poiseuille[76] and Liebig[77] both advanced the theory that the
purgative action of salts was due to their power of attracting water
into the lumen of the intestine, i.e., to their power of endosmosis.
This seemed at first sight to be very satisfactory and to account
well for the increased amount of fluid in the faeces following the
administration of a saline cathartic. The theory did not, however,
take into consideration other substances whose osmotic power is as
great as that of the purgative salts, but which have no purgative
action whatever. It was later, however, supported by Rabuteau[78] in
an experiment in which he claimed to have found that the intravenous
injection of a large quantity of sodium sulphate produced constipation,
while the same salt given by mouth causes purgation. This he ascribed
to the flow of fluid towards the salt in each case due to its osmotic
pressure. This experiment lacks confirmation, and indeed it has been
shown above that sodium sulphate and other saline cathartics produce
increased peristalsis and in some cases increase of fluid in the
intestine when introduced intravenously or applied on the serous
surfaces of the intestine. And these evidences of a purgative action
appear much more rapidly and with smaller doses than when the salt is
placed in the lumen of the intestine. Claude Bernard[79] states in
his criticism of this theory that the intravenous injection of sodium
sulphate causes purgation, and further draws attention to the fact that
on this theory of the endosmotic action of cathartics, sugar, which has
a high osmotic power, should be among the more powerful purgatives.
It was further shown by other investigators that of several purgative
salts, the most powerful was not the one with the highest osmotic power.

Headland,[80] believing that all medicines must first pass into the
circulation before they act, claimed that the saline purgatives are
absorbed from the intestine and are again excreted lower down in the
intestine, and in being excreted they stimulate the glands to secrete.

A little later than this it was shown by Moreau[81] and others that
solutions of purgative salts placed in loops of intestine which
had been tied off caused an increased secretion of fluid into the
intestine. Brieger[82] further confirmed this with better methods and
showed that the fluid was a real secretion, and not an inflammatory
exudate, or a transudation.

Thiry in a series of experiments was unable to produce increased
secretion of fluid from a Thiry-Vella fistula by the introduction of
sulphate of magnesia. He therefore concludes that the action of saline
cathartics is due solely to an increase in peristaltic activity.
Radziejewski[83] held a similar theory and made many experiments in
an attempt to prove that an increase in peristaltic activity was the
main result of the administration of a saline purgative. In connection
with this it may be noted that van Braam-Houckgeest[84] concluded from
his experiments that saline purgatives do not increase the peristaltic
activity of the intestine. It is difficult to imagine how these results
could be obtained.

Hay[85] quotes Aubert, Buchheim, and Wagner as holding the theory
that in addition to causing an increased peristalsis, the salt is
slowly absorbed, and tends to prevent the absorption of fluid from the
intestine. This theory was held also by Schmiedeberg,[86] who claimed
that the purgative salts were absorbed with difficulty and reached the
lower parts of the intestine unchanged. In the large intestine the
salts, according to this hypothesis, prevent the faeces from becoming
compact by inhibiting the absorption of water from the lumen. This
explanation of the action of cathartic salts has been widely accepted
and has been supported by Wallace and Cushny,[87] who claim in addition
that the salts of acids which form insoluble compounds with calcium
are especially active in inhibiting the absorption of fluids from the
intestine.

Loeb in studying the action of salts in the production of muscular
twitchings in voluntary muscles, and of hypersensitiveness of the skin
and nervous elements, recognized the fact that the salts which had
these actions included those commonly known as saline purgatives. He
says in this connection: “I will not deny the effect of these salts
upon the phenomena of absorption of water from the intestine, but it
is obvious from our experiments that the same salts must increase the
irritability of the nerves and muscles of the intestine, and that this
must facilitate the production of peristaltic motions, possibly through
the mechanical or contact stimuli of the faeces upon the nerve endings
or the muscular wall of the intestine.”[88]

My own experiments which I have described above support this suggestion
of Loeb’s. In the first place it was found that the subcutaneous
or intravenous injection of one of these salts, especially sodium
citrate, caused muscular twitchings in the living rabbit. This had
already been done by Loeb in the frog. In both cases the injection of
calcium chloride inhibits the twitchings. As shown above, there are
produced in a rabbit by such an injection of a purgative salt not only
muscular twitchings, but also increased peristaltic movements, and an
increased flow of fluid into the intestine. The subsequent injection
of calcium chloride was shown to inhibit both the increased secretion
and the increased movements of the intestine. There thus seems to be a
very distinct analogy between the action of these salts in producing
twitchings in voluntary muscles and the production of their purgative
effect; and a similar analogy between the suppression of the former
and the suppression of the latter by calcium chloride. One is tempted
to suppose that these purgative salts act by removing calcium from
the tissues, as suggested by Loeb, in the production of muscular
twitchings, since they are all calcium precipitants. There is, however,
no direct proof of this, and other saline purgatives such as BaCl_{2}
and Hg_{2}Cl_{2} certainly have an action which is independent of
calcium.

There thus seems to be produced by saline purgatives a condition of
increased irritability in the intestine analogous to the increased
irritability produced in the voluntary muscles. As a result of this
the two main activities of the intestine are increased, namely, the
peristaltic activity and the secretory activity. The action of the
saline purgative, then, as far as we know, consists of two main parts.
The peristaltic movements are greatly increased in rapidity and force,
and the faeces are carried rapidly from the upper to the lower parts of
the intestine. They are thus passed through the large intestine in so
short a time that the fluid they already contain has not time in which
to be reabsorbed, a process which apparently takes place normally in
the large intestine. At the same time there is a much larger quantity
of fluid secreted into the lumen of the intestine than takes place in
the normal animal. The faeces which are thus forced rapidly through the
gut by the increased peristaltic movements are more fluid than normal.
This together with the rapid passage of the faeces accounts for their
fluid character when a saline purgative is given.

Whether or not the saline purgatives also inhibit the absorption
of fluid from the intestine cannot be stated with certainty. The
experiments of Wallace and Cushny leave out of account the increased
secretion of fluid into the intestine caused by the purgative, a
process which undoubtedly takes place. Thus in comparing the amount of
NaCl, and the amount of a saline purgative absorbed in a given time
from separate loops under the same conditions, it is not surprising
that the amount of NaCl solution found in the loop after the experiment
is less than the amount of purgative solution left. If the quantities
of the two salts were equal in the beginning and an equal amount were
absorbed, there would still be more fluid left in the loop containing
the purgative on account of the secretion of fluid into the loop which
was caused by the purgative, and not by the NaCl.

With regard to the mode in which the salt must be administered it is
quite clear that it is not necessary to place it in the stomach or the
lumen of the intestine. As shown above, the action is more rapid and
more powerful when the solution is injected into the blood, or applied
locally to the peritoneal surface of the intestine. Nor is the action
due to its being secreted again into the lumen of the intestine,
because the action is almost immediate when the solution is poured on
the outside of the loops, and only takes place after several minutes
when placed in the lumen. If injected into the blood the action is
slower than when the solution is applied to the serous surfaces of the
intestine. In the former case every opportunity would be afforded for
its rapid excretion into the intestine if that were a factor. It is
evident that the solution must be absorbed into the blood and bathe the
tissues just as a solution surrounds a muscle which is immersed in it.

As to the tissues in the intestine which are primarily affected, it
is impossible to make a definite statement. The muscle and glands
cannot be at all separated from the complex nervous mechanism of the
intestine, and it is necessary to take the whole as an organ made up of
many tissues and affected in definite ways by certain solutions.

It is interesting in this connection to again note the effect of these
salts on the secretion of urine. It is well known that practically all
of them are diuretics, when introduced with a considerable amount of
fluid. And even when the flow of urine has been greatly increased by
the injection of m/6 NaCl solution, it can be still further augmented
by the addition of, _e.g._, sodium citrate to the injection fluid.
These salts constitute the well known class of saline diuretics. All
salts do not, however, belong to this class, as is often stated.
Calcium chloride, magnesium chloride, and to some extent strontium
chloride exert exactly the opposite effect, inhibiting the action of
the diuretics and diminishing the flow of urine. These salts might
be termed antidiuretics. There is thus an entire analogy between the
action of the saline diuretics on the kidney and that of the saline
purgatives on the intestine, and also the action of calcium and
magnesium is the same in both cases. And the analogy can be traced
farther back to the production and inhibition of muscular twitchings in
voluntary muscles, which was demonstrated by Loeb.

The actual mechanism of the secretion of fluid into the intestine is
difficult to determine. It seems improbable that a change in blood
pressure plays any very important rôle, if indeed it has an influence
at all. There is much evidence to show that many glands consisting
of cells resembling those of the intestine roughly, secrete their
characteristic fluids quite independently of blood pressure. In _Sida
crystallina_, a small fresh-water crustacean, it was found[89] that
if a small quantity of one of the saline purgatives or of BaCl_{2} or
pilocarpine be added to the water in which these crustaceans are lying,
there is not only a rapid increase of intestinal movement and a rapid
evacuation of faeces, but there is also an increased secretion of fluid
into the intestine, so that the whole lumen becomes filled with a pale
greenish fluid. It was pointed out further that in this organism there
is no closed blood vascular system, the blood simply running in wide
channels in more or less definite directions. There can therefore exist
nothing here comparable with the blood pressure of higher animals, and
yet secretion normally takes place without changes in blood pressure.
Further, it can be greatly increased by chemicals without an increase
in blood pressure being possible. A similar secretion without blood
pressure as a causative factor is seen in the skin of the common slug
(Ariolimax). Here the secretion of the skin may be markedly increased
by the injection or local application of a solution of any of the
saline purgatives. This takes place equally well when the heart of the
animal is removed, and also in an isolated portion of the animal, or in
a piece of the skin cut off with the scissors. In these latter cases
there can be no possibility of blood pressure taking a part in the
secretion.

It has been further shown[90] that loops of intestine entirely removed
from the body may be caused to secrete a measurable quantity of fluid
by immersing them in certain purgative solutions, especially those
containing BaCl_{2}. Other solutions such as pure m/6 NaCl do not cause
this secretion, although active peristaltic movements go on in NaCl.
In this case the secretion must be entirely independent of the blood
pressure. Pilocarpine also in the salivary gland causes an enormous
increase in the secretion, without raising the blood pressure in the
carotid.

It is certain from these facts that in many glands secretion is quite
independent of any change in blood pressure; and it seems probable that
such changes must play a very subordinate part in the secretion of
fluid from the intestine.

On the other hand, it is to be noted that in many instances muscular
and secretory activities are controlled by the same conditions.
There seems to be a common factor in the production of the two
functions. Saline purgatives produce not only muscular activity, but
also increased secretion; and calcium and magnesium are capable of
inhibiting both. Atropin also quiets the movements of the intestine,
and at the same time is conspicuous in suppressing the secretion.
Section of the splanchnic nerves causes not only increased muscular
movements, but an increased secretion of fluid in the intestine. These
instances could be greatly increased in number. From them it seems
that something exists in common in muscular movements and in glandular
activity. What first suggests itself is that the gland cells themselves
are made to contract rhythmically by the various conditions which cause
rhythmical contractions in muscle. That the stimulus for this must
be greater in the case of secretion is shown by the fact that in the
intestine peristaltic movements may be maintained in a solution (m/6
NaCl) in which no secretion takes place. It seems not at all improbable
that one factor in the production of secretory activity is dependent on
a property of the gland cell closely related to muscular contractility.

A further factor is suggested by the action of certain diuretics.
In the kidney the changes in the quantity of blood flowing through
the organ and to some extent changes in blood pressure influence the
flow of urine. The diuresis produced by such substances, however, as
saponin, digitalin, potassium chlorate, etc., probably depends on
an increase in permeability of the capsule of Bowman. As shown[91]
recently, these substances produce haemolysis, and are also strong
diuretics. Calcium chloride, which inhibits the flow of urine produced
by them, inhibits also the haemolysis. Haemoglobinuria, which readily
appears with small doses of saponin or digitalin, is inhibited by
simultaneously injecting calcium chloride. There thus seems to be
something in common between haemolysis and diuresis; and what suggests
itself as most probable is that the permeability of the red blood
corpuscle, as well as that of the kidney cell is increased, so that on
the one hand haemoglobin escapes into the blood (is secreted into the
blood), and the amount of urine on the other hand passing through the
kidney cell is increased. Calcium, according to the same idea, would
decrease the permeability in both cases.

In secretion we have therefore among other things two factors which
probably play a rôle, namely, a property of the gland cell resembling
that of muscular contractility and controlled in many cases by the
same conditions, and a change in permeability of the cells which are
secreting. In the kidney there is a third factor dependent on the flow
of blood through the organ. A continuous supply of blood is of course
necessary in all glands for a continued secretion.


FOOTNOTES:

[76] Recherch. expériment. sur les mouvements des liquides dans les
tubes de petits diamètres, Paris, 1828. Quoted from Hay.

[77] Über die Saftbewegung, 1848.

[78] L’Union médicale, 1871, 50, 51. Gaz méd. de Paris, 1879.

[79] Substances toxiques et médicamenteuses, 1857.

[80] Action of Medicines, 1867.

[81] Archiv. général d. médicine, VI Série f. XVI, 1870. Centralbl. f.
d. medicin. Wiss., 1868, p. 209.

[82] Arch. f. exp. Path. u. Pharm., Bd. VIII, 1878, S. 355.

[83] Reichert’s u. DuBois-Reymond’s Archiv, 1870, S. 37.

[84] Pflüger’s Archiv, 1872, S. 266.

[85] _Loc. cit._

[86] Arzneimittellehre, Leipzig, 1883.

[87] Amer. Journ. Physiol., 1898, Vol. I, p. 411.

[88] LOEB: Decennial Publications, University of Chicago, Vol. X, 1902,
p. 10.

[89] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. II, 1905, p. 65.

[90] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. I, 1904, p. 115.

[91] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. II, 1905, p. 93.




                              CHAPTER X.

           Possible Therapeutic Value of These Experiments.


It at once suggests itself to the physician that some clinical use
might be made of the facts outlined above. If such striking results can
be obtained in a rabbit it is possible that some modifications of the
use of these saline purgatives might be made in the human being.

If in the first place it is found that subcutaneous or intravenous
injections of saline purgatives are effective in man, there arise in
both medical and surgical practice occasions in which these methods
of administration would be of the greatest advantage. It is to be
remembered in this connection that the administration by these methods
of MgSO_{4} is especially dangerous. This salt when rapidly absorbed
seems to be very poisonous. Rabbits frequently die in a few minutes
after an intravenous injection of a quantity relatively small as
compared with the amount of Na_{2}SO_{4} which can be given in this
way. Barium chloride is extremely active as a subcutaneous purgative,
but should be used with the greatest caution and in very minute
quantities on account of its very poisonous character. I can give no
idea of the dose that might be given to a human being without danger. A
rabbit usually does not recover from a subcutaneous injection of 3 c.c.
m/8 BaCl solution.

The fact that saline purgative solutions applied to the peritoneal
surfaces of the intestine act very rapidly may suggest some use in
abdominal surgery for this method. If it were desirable to have
evacuation of the bowel rapidly follow an abdominal operation this
procedure might be resorted to. An isotonic solution (m/6) of sodium
sulphate or sodium citrate would be most favorable for this purpose.

The possible uses to which our knowledge of the action of calcium
may be put has aroused some discussion. The fact that it suppresses
muscular and nervous irritability (Loeb), and as shown in the
experiments above, inhibits the muscular and glandular activity of
the intestine, as well as the secretory activity of the kidney, makes
it seem probable that some practical use may be made of it in certain
conditions in the human being. The most important of these conditions
is perhaps the persistent diarrhœa which sometimes accompanies
disorders of an hysterical or neurasthenic sort. There have already
come under my notice several cases of diarrhœa of nervous origin which
were quite uncontrolled by morphine preparations. These cases were
apparently entirely relieved by calcium chloride given for only a few
days. (grs XX t.i.d.) Whether a large number of similar patients will
show the same results remains to be seen. The treatment is evidently
to be applied to only a small class of patients, roughly those cases
of persistent diarrhœa of apparently nervous origin, which cannot be
influenced by opiates.

When rectal infusions of NaCl are not retained it is possible by adding
CaCl_{2} to the solution to stop the movements of the rectum which
cause their expulsion. Enemata of NaCl containing CaCl_{2} are retained
much better than those of pure NaCl.

The marked action of calcium on the kidney suggests that certain
conditions might arise where it could be made use of. In nervous
polyuria it can be given with benefit; and although we know practically
nothing as to the etiology of diabetes insipidus, it is possible that
calcium might be employed with advantage to stop the abnormal flow of
urine.

With regard to general conditions such as the muscular and nervous
irritability accompanying hysterical and neuraesthenic disturbances
little can be said as to the possible value of calcium. Loeb drew
attention to the possibilities of its being of use in these diseases,
but there is not sufficient evidence to make any statement concerning
it. The extreme irritability which is present in some types of insanity
might also be tested in this respect.

Calcium might also be of benefit in asthma where the two distressing
symptoms are spasmodic contractions of the bronchioles and a
hypersecretion from the mucous membrane of the larger and smaller
bronchi. Judging by analogy from the experiments described above,
calcium should not only relieve the muscular contractions but also
inhibit the secretion.

These suggestions are made simply in the hope of stimulating clinical
research in this direction.

Wright has recently stated that calcium relieves urticaria, a
circumstance which he refers to the influence of calcium on the
coagulability of the blood, which he says is diminished in this
condition. It seems more probable from the above experiments that the
calcium inhibits the secretion or passage of fluid from the lymph
vessels to form the vesicles.




                              CHAPTER XI.

             The Action of Purgatives of Vegetable Origin.


This group of purgatives, as far as its general properties are
concerned, is so well described in many text-books that it is
unnecessary here to go into the details of their preparation and the
commoner characteristics of each. Certain points which have come up in
connection with my own experiments, however, may be briefly described
here.

Cascara Sagrada is prepared in many ways, but the most favorable
preparation for experiment is the dried extract. This is the dark
yellow powder familiar in commerce. It is found that in shaking
this powder in distilled water it is almost entirely insoluble. The
result is a dirty yellow mixture, the filtrate from which gives an
acid reaction. This suggested neutralizing the mixture or making it
alkaline. A small amount of sodium bicarbonate was added, and the
powder immediately went into solution, producing a clear dark brown
fluid.[92] A similar result was obtained by adding sodium hydrate.
It was found that ¹⁄₂ g. of the dried extract could be dissolved in
25 c.c. m/24 NaHCO_{3}. This solution in NaHCO_{3}, is practically
neutral. If a few drops of dilute H_{2}SO_{4} be added a yellow
precipitate at once appears giving a mixture or suspension similar
to that originally obtained by adding the powder to distilled water.
The addition of NaHCO_{3} will again produce the characteristic dark
brown solution. The extract is much more readily soluble in a stronger
solution of NaHCO_{3}.

The dried extract is thus soluble only in a neutral or alkaline fluid.
It is insoluble in distilled water on account of the free acid which is
present in the powder.

Cascara extract is readily soluble in the intestinal juice of a rabbit,
a characteristic dark brown clear solution being obtained. On the other
hand, it is insoluble in the gastric juice, and an alkaline solution
added to the gastric juice is at once precipitated.

It was found that the intravenous injection of 1 c.c. of a 2% solution
of cascara extract in m/25 NaHCO_{3} produces within a minute very
strong peristaltic movements in the intestine. A similar injection of
the same amount of m/25 NaHCO_{3} alone produces no such result, though
stronger solutions of NaHCO_{3} cause a slight increase in intestinal
movements. It is therefore the cascara in solution which produces these
strong contractions.

A somewhat larger quantity of the cascara solution injected
subcutaneously produces increased peristaltic activity after an
interval of several minutes.

If the cascara solution be applied directly to the serous surfaces
of the intestine, very strong contractions and peristaltic movements
result in 2 or 3 minutes. A solution of m/25 NaHCO_{3} alone produces
very slight movements when applied in this way. These can, however, be
readily distinguished from those produced by cascara. The latter are
much more powerful, are slower in developing, and can be only partially
inhibited by m/6 CaCl_{2}. The movements following the application
of pure NaHCO_{3} solution, however, are weak, they appear almost
immediately, and can be entirely suppressed by the application of m/6
CaCl_{2} solution.

When the cascara solution is placed in the stomach no movements appear
in the intestine even after 15-30 minutes. The acid of the gastric
juice has evidently precipitated the cascara, which cannot act until
it is passed on into the intestine where it may be dissolved in the
alkaline juice of the intestine. If instead of placing the solution in
the stomach it is injected directly into the small intestine, increased
peristaltic movements begin within 5 minutes. Here it evidently remains
in solution and is absorbed. It is for this reason that in human
beings cascara taken by mouth acts only after several hours. It is
precipitated in the stomach and must reach the intestine before it is
dissolved and absorbed.

In addition to the increased peristaltic activity caused by the
cascara, there seems to be also an increase in the secretion of fluid
into the lumen. One or two hours after the injection 20-30 c.c. fluid
could be collected from the small intestine. Without the purgative it
is rarely possible to obtain more than 5 to 10 c.c.

It was found that calcium chloride has only a very transient effect
in inhibiting the increased movements produced by cascara. For 2 or 3
minutes following the injection of CaCl_{2} the movements were usually
quieted, but they rapidly began again and continued as vigorously as
before.

The behavior of rhubarb is in every way similar to that of cascara. It
is less readily soluble, but the solution acts in a way quite like that
described for cascara.

It is further well known that aloin injected subcutaneously causes
increased peristalsis. A study has recently been made of certain
constituents of the derivatives of the aloes group of purgatives.
Esselmont,[93] following the work of Tschirch,[94] experimented with
a number of substances obtained from these purgatives. Aloëemodin
is present not only in aloes, but also in Cascara sagrada and senna
leaves. A small amount of this substance acts as a purgative.
Alochrysin, aloingrin, barbaloin, all act as purgatives. Chrysophanic
acid, which is found in aloes, rhubarb, and senna is a mild purgative.
It is of interest to note that each of these substances is either a
di-or tri-oxymethylanthrachinon. They owe their purgative action,
according to Tschirch, to their containing the oxymethylanthrachinon
group.

Some experiments[95] which I recently made on a jellyfish (Polyorchis)
with some of the vegetable purgatives are of interest. They were
suggested by the experiments of Loeb[96] on the effect of various
salts on the isolated center of the animal and of a related form
(Gonionemus). When separated from the margins the bell-like centers of
these jellyfish do not beat in pure sea-water. In case of Gonionemus
it was found that the addition of one of a number of salts (calcium
precipitants) caused the center to beat. This group of salts includes
the so-called saline purgatives.

The methods used in the experiments with vegetable purgatives were
practically the same as those used by Loeb. The animal was bisected
just above the ring of sense organs in order to entirely remove the
margin containing the main nervous system. The center was then placed
in mixtures of sea-water and solutions of the purgatives. The center
never beats in pure sea-water, but was found to beat vigorously in
sea-water to which a small quantity of a solution of cascara, rhubarb,
aloin, podophyllin, or colocynth had been added. It was necessary to
dissolve the cascara and rhubarb extracts in m/24 NaHCO_{3}, since they
are not soluble in pure water. The centers do not beat in sea-water to
which pure m/24 NaHCO_{3} has been added in quantities equivalent to
those added with the purgative solution.

A solution of ¹⁄₄ g. cascara extract was made in 50 c.c. m/24
NaHCO_{3}. It was found that a mixture of 25 c.c. sea-water + 2 c.c. of
this cascara solution was the most favorable for producing rhythmical
contractions in the isolated center of Polyorchis. Contractions lasted
10-15 minutes.

A solution of rhubarb extract of the same strength was made. The
optimal mixture in this case is 25 c.c. sea-water + 0.5 c.c. or 1 c.c.
rhubarb solution. In this mixture the contractions develop quickly and
last 15 minutes or more.

With aloin the concentration of the purgative needed to produce
optimal results was somewhat greater than in cascara or rhubarb.
Colocynth and podophyllin act similarly, but the contractions soon
cease.

These vegetable purgatives thus act on the jellyfish, Polyorchis, in a
way quite similar to that described by Loeb for saline purgatives.

Pilocarpine, though not used as a purgative on account of its special
action on other organs of the body, has a powerful action also on
the intestine. Its influence on the intestine is much like that of
barium chloride. It causes violent contractions of the musculature of
the gut and very active peristaltic movements. This is the case in
whatever way the substance is administered. A few drops of a ¹⁄₁₀%
solution of pilocarpine hydrochlorate in distilled water poured on
the serous surfaces of the rabbit’s intestine brings about almost
immediately violent peristaltic movements. In addition to this there is
an increase in the amount of fluid secreted into the intestine, 20-30
c.c. gathering in the small intestine in an hour. The evacuation of
faeces takes place in about three-quarters of an hour. These may be
of a semifluid character, and with larger doses resemble the faeces
produced by BaCl_{2}. The antagonism between pilocarpine and CaCl_{2}
is incomplete. CaCl_{2} is capable of inhibiting only temporarily the
movements caused by pilocarpine.

It is interesting to note the marked purgative effect of pilocarpine
in a small fresh-water crustacean (_Sida crystallina_). This animal,
which has been spoken of in previous chapters belongs to the Cladocera.
The intestine extends in a fairly straight line throughout the body,
bending downward at the post abdomen to open to the outside. At the
anterior end is a slight dilatation which may represent the stomach.
From this there open two diverticula or coeca which seem to be of a
glandular nature, and are sometimes spoken of as digestive glands.
They are usually filled with a greenish fluid. The intestine is
always filled with brown faeces which are normally expelled in small
quantities, only at considerable intervals. Slight peristaltic waves
are commonly seen in the lower part of the intestine.

These animals were placed in various solutions, and it was found[97]
that pilocarpine hydrochlorate, aloin, cascara, as well as barium
chloride, sodium citrate, sulphate, and fluoride, caused an increased
peristaltic activity of the intestine, and a rapid expulsion of faeces,
so that in a very short time the entire intestine was empty. At the
same time the intestine becomes filled with a greenish fluid similar
to that seen in the diverticula. This fluid may be also expelled and
replaced again. It is evidently secreted by the intestine or by the
diverticula as a result of the purgative action. Very dilute solutions
of pilocarpine are sufficient to bring about this effect. In a 1%
solution the action is very rapid, and evacuation of faeces may be
brought about by a mixture of 1 c.c. 0.1% pilocarpine in 10 c.c. water.
This takes place within 20 minutes.

An attempt was made to determine whether or not CaCl_{2} is capable
of inhibiting the action of pilocarpine. The experiments on rabbits
in this respect were unsatisfactory. It was found that the greatest
dilution at which expulsion of faeces in Sida could be caused in a
short period of time was 1 c.c. 0.1% pilocarpine + 10 c.c. water.
Animals were placed in a mixture of 1 c.c. 0.1% pilocarpine + 10 c.c.
m/6 CaCl_{2}. These behaved exactly as though the water had not been
replaced by CaCl_{2}. In other words, the presence of the CaCl_{2} did
not delay at all the action of the pilocarpine. This was repeated many
times, and it seems that in Sida at least the action of pilocarpine is
not at all antagonized by calcium chloride. In a mixture, however, of
10 c.c. 1% atropin sulphate + 1 c.c. 0.1% pilocarpine no evacuation of
faeces took place and there was no increase in peristalsis.


FOOTNOTES:

[92] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. I, p. 163.

[93] Archiv f. exp. Path. u. Pharm., Bd. 43, 1900, S. 274.

[94] Schweiz. Wochenschrift für Chemie and Pharmacie, 1898, No. 23.

[95] To appear shortly in Journal of Biological Chemistry.

[96] _Loc. cit._

[97] MACCALLUM, J. B.: University of California Publications, Vol. II,
1905, p. 65.




                          Transcriber’s Notes

Punctuation and spacing errors have been corrected.

Page 33: In the footnote, “no interval beteen” changed to “no interval
between”



*** END OF THE PROJECT GUTENBERG EBOOK ON THE MECHANISM OF THE PHYSIOLOGICAL ACTION OF THE CATHARTICS ***


    

Updated editions will replace the previous one—the old editions will
be renamed.

Creating the works from print editions not protected by U.S. copyright
law means that no one owns a United States copyright in these works,
so the Foundation (and you!) can copy and distribute it in the United
States without permission and without paying copyright
royalties. Special rules, set forth in the General Terms of Use part
of this license, apply to copying and distributing Project
Gutenberg™ electronic works to protect the PROJECT GUTENBERG™
concept and trademark. Project Gutenberg is a registered trademark,
and may not be used if you charge for an eBook, except by following
the terms of the trademark license, including paying royalties for use
of the Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is very
easy. You may use this eBook for nearly any purpose such as creation
of derivative works, reports, performances and research. Project
Gutenberg eBooks may be modified and printed and given away—you may
do practically ANYTHING in the United States with eBooks not protected
by U.S. copyright law. Redistribution is subject to the trademark
license, especially commercial redistribution.


START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE

PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK

To protect the Project Gutenberg™ mission of promoting the free
distribution of electronic works, by using or distributing this work
(or any other work associated in any way with the phrase “Project
Gutenberg”), you agree to comply with all the terms of the Full
Project Gutenberg™ License available with this file or online at
www.gutenberg.org/license.

Section 1. General Terms of Use and Redistributing Project Gutenberg™
electronic works

1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand, agree to
and accept all the terms of this license and intellectual property
(trademark/copyright) agreement. If you do not agree to abide by all
the terms of this agreement, you must cease using and return or
destroy all copies of Project Gutenberg™ electronic works in your
possession. If you paid a fee for obtaining a copy of or access to a
Project Gutenberg™ electronic work and you do not agree to be bound
by the terms of this agreement, you may obtain a refund from the person
or entity to whom you paid the fee as set forth in paragraph 1.E.8.

1.B. “Project Gutenberg” is a registered trademark. It may only be
used on or associated in any way with an electronic work by people who
agree to be bound by the terms of this agreement. There are a few
things that you can do with most Project Gutenberg™ electronic works
even without complying with the full terms of this agreement. See
paragraph 1.C below. There are a lot of things you can do with Project
Gutenberg™ electronic works if you follow the terms of this
agreement and help preserve free future access to Project Gutenberg™
electronic works. See paragraph 1.E below.

1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the collection
of Project Gutenberg™ electronic works. Nearly all the individual
works in the collection are in the public domain in the United
States. If an individual work is unprotected by copyright law in the
United States and you are located in the United States, we do not
claim a right to prevent you from copying, distributing, performing,
displaying or creating derivative works based on the work as long as
all references to Project Gutenberg are removed. Of course, we hope
that you will support the Project Gutenberg™ mission of promoting
free access to electronic works by freely sharing Project Gutenberg™
works in compliance with the terms of this agreement for keeping the
Project Gutenberg™ name associated with the work. You can easily
comply with the terms of this agreement by keeping this work in the
same format with its attached full Project Gutenberg™ License when
you share it without charge with others.

1.D. The copyright laws of the place where you are located also govern
what you can do with this work. Copyright laws in most countries are
in a constant state of change. If you are outside the United States,
check the laws of your country in addition to the terms of this
agreement before downloading, copying, displaying, performing,
distributing or creating derivative works based on this work or any
other Project Gutenberg™ work. The Foundation makes no
representations concerning the copyright status of any work in any
country other than the United States.

1.E. Unless you have removed all references to Project Gutenberg:

1.E.1. The following sentence, with active links to, or other
immediate access to, the full Project Gutenberg™ License must appear
prominently whenever any copy of a Project Gutenberg™ work (any work
on which the phrase “Project Gutenberg” appears, or with which the
phrase “Project Gutenberg” is associated) is accessed, displayed,
performed, viewed, copied or distributed:

    This eBook is for the use of anyone anywhere in the United States and most
    other parts of the world at no cost and with almost no restrictions
    whatsoever. You may copy it, give it away or re-use it under the terms
    of the Project Gutenberg License included with this eBook or online
    at www.gutenberg.org. If you
    are not located in the United States, you will have to check the laws
    of the country where you are located before using this eBook.
  
1.E.2. If an individual Project Gutenberg™ electronic work is
derived from texts not protected by U.S. copyright law (does not
contain a notice indicating that it is posted with permission of the
copyright holder), the work can be copied and distributed to anyone in
the United States without paying any fees or charges. If you are
redistributing or providing access to a work with the phrase “Project
Gutenberg” associated with or appearing on the work, you must comply
either with the requirements of paragraphs 1.E.1 through 1.E.7 or
obtain permission for the use of the work and the Project Gutenberg™
trademark as set forth in paragraphs 1.E.8 or 1.E.9.

1.E.3. If an individual Project Gutenberg™ electronic work is posted
with the permission of the copyright holder, your use and distribution
must comply with both paragraphs 1.E.1 through 1.E.7 and any
additional terms imposed by the copyright holder. Additional terms
will be linked to the Project Gutenberg™ License for all works
posted with the permission of the copyright holder found at the
beginning of this work.

1.E.4. Do not unlink or detach or remove the full Project Gutenberg™
License terms from this work, or any files containing a part of this
work or any other work associated with Project Gutenberg™.

1.E.5. Do not copy, display, perform, distribute or redistribute this
electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1 with
active links or immediate access to the full terms of the Project
Gutenberg™ License.

1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form, including
any word processing or hypertext form. However, if you provide access
to or distribute copies of a Project Gutenberg™ work in a format
other than “Plain Vanilla ASCII” or other format used in the official
version posted on the official Project Gutenberg™ website
(www.gutenberg.org), you must, at no additional cost, fee or expense
to the user, provide a copy, a means of exporting a copy, or a means
of obtaining a copy upon request, of the work in its original “Plain
Vanilla ASCII” or other form. Any alternate format must include the
full Project Gutenberg™ License as specified in paragraph 1.E.1.

1.E.7. Do not charge a fee for access to, viewing, displaying,
performing, copying or distributing any Project Gutenberg™ works
unless you comply with paragraph 1.E.8 or 1.E.9.

1.E.8. You may charge a reasonable fee for copies of or providing
access to or distributing Project Gutenberg™ electronic works
provided that:

    • You pay a royalty fee of 20% of the gross profits you derive from
        the use of Project Gutenberg™ works calculated using the method
        you already use to calculate your applicable taxes. The fee is owed
        to the owner of the Project Gutenberg™ trademark, but he has
        agreed to donate royalties under this paragraph to the Project
        Gutenberg Literary Archive Foundation. Royalty payments must be paid
        within 60 days following each date on which you prepare (or are
        legally required to prepare) your periodic tax returns. Royalty
        payments should be clearly marked as such and sent to the Project
        Gutenberg Literary Archive Foundation at the address specified in
        Section 4, “Information about donations to the Project Gutenberg
        Literary Archive Foundation.”
    
    • You provide a full refund of any money paid by a user who notifies
        you in writing (or by e-mail) within 30 days of receipt that s/he
        does not agree to the terms of the full Project Gutenberg™
        License. You must require such a user to return or destroy all
        copies of the works possessed in a physical medium and discontinue
        all use of and all access to other copies of Project Gutenberg™
        works.
    
    • You provide, in accordance with paragraph 1.F.3, a full refund of
        any money paid for a work or a replacement copy, if a defect in the
        electronic work is discovered and reported to you within 90 days of
        receipt of the work.
    
    • You comply with all other terms of this agreement for free
        distribution of Project Gutenberg™ works.
    

1.E.9. If you wish to charge a fee or distribute a Project
Gutenberg™ electronic work or group of works on different terms than
are set forth in this agreement, you must obtain permission in writing
from the Project Gutenberg Literary Archive Foundation, the manager of
the Project Gutenberg™ trademark. Contact the Foundation as set
forth in Section 3 below.

1.F.

1.F.1. Project Gutenberg volunteers and employees expend considerable
effort to identify, do copyright research on, transcribe and proofread
works not protected by U.S. copyright law in creating the Project
Gutenberg™ collection. Despite these efforts, Project Gutenberg™
electronic works, and the medium on which they may be stored, may
contain “Defects,” such as, but not limited to, incomplete, inaccurate
or corrupt data, transcription errors, a copyright or other
intellectual property infringement, a defective or damaged disk or
other medium, a computer virus, or computer codes that damage or
cannot be read by your equipment.

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except for the “Right
of Replacement or Refund” described in paragraph 1.F.3, the Project
Gutenberg Literary Archive Foundation, the owner of the Project
Gutenberg™ trademark, and any other party distributing a Project
Gutenberg™ electronic work under this agreement, disclaim all
liability to you for damages, costs and expenses, including legal
fees. YOU AGREE THAT YOU HAVE NO REMEDIES FOR NEGLIGENCE, STRICT
LIABILITY, BREACH OF WARRANTY OR BREACH OF CONTRACT EXCEPT THOSE
PROVIDED IN PARAGRAPH 1.F.3. YOU AGREE THAT THE FOUNDATION, THE
TRADEMARK OWNER, AND ANY DISTRIBUTOR UNDER THIS AGREEMENT WILL NOT BE
LIABLE TO YOU FOR ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL, PUNITIVE OR
INCIDENTAL DAMAGES EVEN IF YOU GIVE NOTICE OF THE POSSIBILITY OF SUCH
DAMAGE.

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you discover a
defect in this electronic work within 90 days of receiving it, you can
receive a refund of the money (if any) you paid for it by sending a
written explanation to the person you received the work from. If you
received the work on a physical medium, you must return the medium
with your written explanation. The person or entity that provided you
with the defective work may elect to provide a replacement copy in
lieu of a refund. If you received the work electronically, the person
or entity providing it to you may choose to give you a second
opportunity to receive the work electronically in lieu of a refund. If
the second copy is also defective, you may demand a refund in writing
without further opportunities to fix the problem.

1.F.4. Except for the limited right of replacement or refund set forth
in paragraph 1.F.3, this work is provided to you ‘AS-IS’, WITH NO
OTHER WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED, INCLUDING BUT NOT
LIMITED TO WARRANTIES OF MERCHANTABILITY OR FITNESS FOR ANY PURPOSE.

1.F.5. Some states do not allow disclaimers of certain implied
warranties or the exclusion or limitation of certain types of
damages. If any disclaimer or limitation set forth in this agreement
violates the law of the state applicable to this agreement, the
agreement shall be interpreted to make the maximum disclaimer or
limitation permitted by the applicable state law. The invalidity or
unenforceability of any provision of this agreement shall not void the
remaining provisions.

1.F.6. INDEMNITY - You agree to indemnify and hold the Foundation, the
trademark owner, any agent or employee of the Foundation, anyone
providing copies of Project Gutenberg™ electronic works in
accordance with this agreement, and any volunteers associated with the
production, promotion and distribution of Project Gutenberg™
electronic works, harmless from all liability, costs and expenses,
including legal fees, that arise directly or indirectly from any of
the following which you do or cause to occur: (a) distribution of this
or any Project Gutenberg™ work, (b) alteration, modification, or
additions or deletions to any Project Gutenberg™ work, and (c) any
Defect you cause.

Section 2. Information about the Mission of Project Gutenberg™

Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new computers. It
exists because of the efforts of hundreds of volunteers and donations
from people in all walks of life.

Volunteers and financial support to provide volunteers with the
assistance they need are critical to reaching Project Gutenberg™’s
goals and ensuring that the Project Gutenberg™ collection will
remain freely available for generations to come. In 2001, the Project
Gutenberg Literary Archive Foundation was created to provide a secure
and permanent future for Project Gutenberg™ and future
generations. To learn more about the Project Gutenberg Literary
Archive Foundation and how your efforts and donations can help, see
Sections 3 and 4 and the Foundation information page at www.gutenberg.org.

Section 3. Information about the Project Gutenberg Literary Archive Foundation

The Project Gutenberg Literary Archive Foundation is a non-profit
501(c)(3) educational corporation organized under the laws of the
state of Mississippi and granted tax exempt status by the Internal
Revenue Service. The Foundation’s EIN or federal tax identification
number is 64-6221541. Contributions to the Project Gutenberg Literary
Archive Foundation are tax deductible to the full extent permitted by
U.S. federal laws and your state’s laws.

The Foundation’s business office is located at 809 North 1500 West,
Salt Lake City, UT 84116, (801) 596-1887. Email contact links and up
to date contact information can be found at the Foundation’s website
and official page at www.gutenberg.org/contact

Section 4. Information about Donations to the Project Gutenberg
Literary Archive Foundation

Project Gutenberg™ depends upon and cannot survive without widespread
public support and donations to carry out its mission of
increasing the number of public domain and licensed works that can be
freely distributed in machine-readable form accessible by the widest
array of equipment including outdated equipment. Many small donations
($1 to $5,000) are particularly important to maintaining tax exempt
status with the IRS.

The Foundation is committed to complying with the laws regulating
charities and charitable donations in all 50 states of the United
States. Compliance requirements are not uniform and it takes a
considerable effort, much paperwork and many fees to meet and keep up
with these requirements. We do not solicit donations in locations
where we have not received written confirmation of compliance. To SEND
DONATIONS or determine the status of compliance for any particular state
visit www.gutenberg.org/donate.

While we cannot and do not solicit contributions from states where we
have not met the solicitation requirements, we know of no prohibition
against accepting unsolicited donations from donors in such states who
approach us with offers to donate.

International donations are gratefully accepted, but we cannot make
any statements concerning tax treatment of donations received from
outside the United States. U.S. laws alone swamp our small staff.

Please check the Project Gutenberg web pages for current donation
methods and addresses. Donations are accepted in a number of other
ways including checks, online payments and credit card donations. To
donate, please visit: www.gutenberg.org/donate.

Section 5. General Information About Project Gutenberg™ electronic works

Professor Michael S. Hart was the originator of the Project
Gutenberg™ concept of a library of electronic works that could be
freely shared with anyone. For forty years, he produced and
distributed Project Gutenberg™ eBooks with only a loose network of
volunteer support.

Project Gutenberg™ eBooks are often created from several printed
editions, all of which are confirmed as not protected by copyright in
the U.S. unless a copyright notice is included. Thus, we do not
necessarily keep eBooks in compliance with any particular paper
edition.

Most people start at our website which has the main PG search
facility: www.gutenberg.org.

This website includes information about Project Gutenberg™,
including how to make donations to the Project Gutenberg Literary
Archive Foundation, how to help produce our new eBooks, and how to
subscribe to our email newsletter to hear about new eBooks.