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.