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of as the growth of protoplasm. We have reason to believe that the rate of
growth of the protoplasm increases more than the rate of flow of fluid as the
stimuli pass from weak to strong.

To account for this on the osmotic theorj^, it must be supposed that only
the outermost portion of the membrane becomes permeable to proteids, so that
the proteid molecules are blocked in their passage, and further that the ratio
of permeability to proteids and to water is greater with strong than Avith weak
stimuli. The theory becomes further complicated, if Ave have to apply it also
to a taking up of proteid during rest (cf. p. 486), Avhen there is no passage of
fluid ; for in this case the inner part of the membrane at least must be im-
permeable to water, whilst the outer part is permeable to proteids.

So far we have assumed that the conditions of the solutions on the two
sides of the membrane are such as would lead to an osmotic flow through it,
directed from its outer to its inner surface. But this is precisely the point it
is difficult to be clear about. There is no obvious reason Avhy the fluid in
contact with surfaces of the membrane bounding the spaces should be A^ery
different from the fluid issuing from the inner surface of the membrane. But
the saliva contains commonly less organic substance and less salts than the
lymph. Why then should fluid pass from the lymph to the saliva ? It can
only be said that it is perhaps possible that a passage both of Avater and salts
might take place if the organic substance in the spaces formed some combina-
tion Avith Avater and salts, of AA^hich at present Ave haA'e not sufficient evidence.

The hypothesis Avhich I haA^e stated above seems capable of being put
to the test of experiment, and of being either proved or disproved. Failing
it, Ave are, I think, driven to suppose — apart from the hypothesis of special
vital activity — that the outer layer of the cell forms a loose chemical combina-
tion with various substances of the lymph, and that these are passed on from
molecule to molecule and disassociated at the inner surface. A process of this
kind forms the basis of the chemical theory of osmosis. And it seems to me
not improbable that such a process occurs in gland-cells, but it is extremely
diflicult to see hoAV to bring any experimental evidence to bear directly on the
question. The investigation appears to demand, as a preliminary, an intimate
knoAvledge of the chemical nature of the membrane. The membrane consists
of protoplasm. And there are fcAv problems in physiology AA^hich appear more
remote from solution than that of the chemical nature of liA'ing substance.



MECHANISM OF SECRETION OF CxASTRIC,
PANCREATIC, AND INTESTINAL JUICES.

By J. S. Edkins.

Contents. — Histological Appearances of tlie Secretory Conditions of the Stomach,
p. 531 — Functions of the Cells and Regions of the Stomach, p. 532 — Methods
of obtaining Gastric Juice, p. 536— Intluence of the Nervous System on Gastric
Secretion, p. 537— Conditions which provoke Secretion, p. 540 — Formation of
the Ferments of Gastric Juice, p. 542 — Formation of Rennin, p. 543 — Variations
in Gastric Juice during Digestion, p. 544 — Histological Appearances of the
Secretory Conditions of the Pancreas, p. 546 — Influence of the Nervous System
upon Pancreatic Secretion, p. 547 — Conditions which provoke the Flow of
Pancreatic Juice, p. 551 — Ferments of the Pancreatic Juice and their Ante-
cedents, p. 551 — Variations in Pancreatic Juice during Digestion, p. 553 —
Evidence of Secretion in the Intestine, p. 554.

The Mechanism of Gastric Secretion.

The histological appearances of the different secretory con-
ditions of the stomach, and the relation of the secretory granules
to the enzyme.— Though the existence of specific granules in secretory
glands had previously been pointed out in connection with the pancreas
and some salivary glands, it was not till 1879 that their existence was
also observed in the secreting cells of the gastric mucous membrane by
Langley and Sewall,^ who showed that the chief or central cells are, in
the resting condition, crowded with conspicuous granules, and that
during digestion the granules in these cells diminish. As far as the
ovoid or border cells are concerned, granules are to be seen in these, but
they are much smaller in size, though quite discrete.

After digestion the cells take on different appearances, which consist
mainly in the decrease of the number of granules. This decrease may
be manifested in two different ways. In the first case, and the more
typical, the outer border of the cell alone may show the lack of granules,
the luminal border retaining them, unless in an extreme condition of
exhaustion. In the second case, there may be a uniform decrease of
granules throughout the cell, accompanied by a diminution in size
of the cell, but unaccompanied by any formation of zones. These two
forms of decrease may occur in different parts of the gastric mucous
membrane of the same animal. Thus in the greater curvature of the
stomach in both the rabbit and guinea-pig there is a formation of zones,
in the cells of the fundus such a division is not seen.

^ "Changes in Pepsin-forming Glands," Journ. Physiol, Cambridge and London, 1S79,
vol. ii.



532 MECHANISAI OF SECRETION OF GASTRIC JUICE.

At the pyloric end of the dog's stomach in the resting or exhausted
state, an appearance is seen which consists of small and obscure granules
somewhat radially arranged, an appearance which bears a slight resem-
blance to that seen m the ducts of salivary glands in the fresh condition.
A very marked difference exists, however, between the pyloric cells and
the cardiac cells, and there seems little doubt that considerable histo-
logical distinction obtains. Nevertheless, attempts have been made by
Ebstein ^ and others to prove the identity of the chief cells of the cardiac
end with the lining cells of the body of the pyloric glands. It may Ije
stated that Langley and Sewall found no difference in the pyloric cells
whether the glands were in a resting or active condition, and other later
observations also show a marked uniformity of appearance in the cells
whatever the secretory condition be.

It may then be regarded as established that a diminution in the
amount of granules characterises the chief cells as digestion advances.
It has, moreover, been shown by Grlitzner ^ and others, that as digestion
advances the fundus glands contain less ferment than in hunger. It is
therefore justifiable to conclude that the granules are in some way
connected with the ferment. In addition to this, we have the fact that
more pepsin can be obtained from the cells of the fundus in the rabbit
than from the greater curvature, and it is in the fundus that the cells
are conspicuously granular. We have, however, to consider that, though
the chief cells will yield pepsin, yet they do not actually contain pepsin.
If the granules then are connected with pepsin, it must be in some
antecedent form. The probable explanation of this is that the granules
of the chief cells consist wholly or in part of pepsinogen, the precursor
of pepsin.

The functions of the different forms of cells and of the different
regions of the stomach. — Heidenhain originated the view that the
chief cells were connected with tlie formation of pepsin, and the border
cells with the formation of the acid of the gastric juice. The arguments
upon which these conclusions are based are not direct, but though really
inferential they appear to be supported by such evidence that but Httle
doubt can be placed upon their accuracy.

The reasons for regarding the chief cells as connected with the
formation of pepsin have been dwelt upon in the previous section. But
is there evidence to disconnect the border cells from this same function ?
The most direct evidence we have is that, in the rabbit, the greater
curvature contains more border cells than any other portion of the
stomach ; the pyloric glands of the smaller curvature contain at most an
occasional border cell here and there, yet the amount of pepsin produced
by the two gland forms is scarcely different. The obvious conclusion is
that the border cells do not form the ferment. On the other hand, it is
noticed that the pyloric secretion is distinctly alkaline if separated from
the rest of the stomach ; this is affirmed by Klemensiewicz,^ Heidenhain,^
and, later, Ackermann.^ Apparently, therefore, such cells as are present

^_Arch.f. mikr. AnaL, Bonn, 1870, Bd. vi.

; '^Untersucli. ueLcr d. Bildung ii. Aussch. des Pepsins," Breslau, 1875.
■^"Ueberden Succus pyloricus," Sitzungsb. d. k. Akad. d. JVissensch., Wien, 1875,
]3d. Ixxi.

^ "Ueber die Pepsinbilduug in den Pylorasdriisen," Arch. f. d. ges. Physiol., Bonn,
1878, Bd. xviii.

^ " Experinieutelle Beitriige zui' Jvenntniss des Pylorussecretes beim Hunde," Skandiii.
Arch./. Physiol, Leipzig, 1894, Bd. v.



FUNCTIONS OF DIFFERENT FORMS OF CEILS. 533

in the pyloric region do not contribute to the formation of acid.
In the frog the source of the ferment is an alkaline juice fur-
nished by tiie oesophageal glands, whilst the cells in the stomach bear
resemblance to the border" cells of the mammal, and here alone the
acid of the juice is secreted. The deeper parts of the cardiac glands,
where there are fewer border cells, do not give an acid reaction, the
acid reaction being evident only at the mouths and upper parts of the
glands.

Claude Bernard ^ attempted to mark out the place where the free
hydrochloric acid first appeared, by injecting intravenously a solution of
ferric lactate followed by a solution of potassium ferrocyanide (these two
compounds react with the production of Prussian blue only in the
presence of a mineral acid). After the lapse of three quarters of an
hour the animal was killed and the tissues examined. A blue pre-
cipitate was only observed on the surface of the mucous membrane
of the stomach, especially in the neighbourhood of the lesser cur-
vature, but no trace of blue in the glands. This experiment might,
at first sight, be taken as indicating that the hydrochloric acid is first
set free on the stomach itself, and is not formed in the cells of the
gastric glands. Such a conclusion would be unwarranted. What the
experiment does teach is that tlure, is no accumulation of acid in the
cells, but that the acid as rapidly as it is formed is thrown out of the
cells as a secretion.

Briicke^ tried to solve the same problem by exposing the stomach of
an animal in which digestion was actively going on, and carefully
removing all but the mucous coat ; both in the pigeon and in the rabbit
the reaction of the exposed mucous layer to litmus paper was found to
be faintly alkaline or very faintly acid, practically neutral, but on
testing the inner surface of the mucous membrane it was, as usual,
intensely acid. This again is an experiment which, had it given a
positive result, would have shown conclusively that the acid was
secreted by the gland-cells ; but, giving as it did a doubtful or negative
result, it teaches little, and by no means proves the statement that
the acid is not formed in the glands but in the stomach. In cutting
into the stomach wall in this manner, sources of alkali are tapped
in the small blood vessels and lymph spaces which are capable of
supplying more than sufficient alkali to neutralise any acid in the
gland lumina.

Brilcke himself was not satisfied with this experiment, and attacked
the problem by another method, which gave him results from which he
concluded that the acid is really formed in the glands, and not in the
stomach cavity. In birds, the gastric glands are compound glands
forming flask-shaped bodies large enough to be easily seen without
magnification. These compound glands possess also a flask-shaped
cavity communicating with the stomach cavity by a comparatively
narrow duct. Into this central cavity of the gland the secretion passes.
Briicke took the secreting stomach of a fowl which had been killed
during digestion, washed it out with magnesia suspended in water to
neutralise the free acid on the surface of the mucous membrane, and
sought out one of the above-described glands filled with secretion.

^ " Lecoiis sur les propriet^s pliysioL," Paris, 1859, vol. ii.

- Sitzungsh. d. 7c. Akad. d. TVissensch., Wim, 1859, Bel. xxxvii. ; " Yorlesungen,"
Aufl. 4, Bci i. S. 306,



534 MECHANISM OF SECRETION OF GASTRIC JUICE.

This he cut across, and tested the reaction of the fluid in its cavity. He
found it as strongly acid as the secretion inside the stomach cavity.
This experiment may be taken to show that the acid is secreted in the
glands, but is continually being carried away by the stream of secretion.
It might be objected against this experiment, that the fluid in the cavity
of the compound gland is in communication with the stomach cavity
and is acid by reason of admixture, but the communicating duct is too
small to make this probable ; moreover, there must be a continual
stream flowing during secretion in the opposite direction from gland
cavity to stomach cavity. That the gland cavity is not passively filled
with secretion from the general stomach cavity, is also shown by the
fact that some of these glands are swollen out with secretion while
others are empty. It may be taken, then, that the gastric juice is acid
as secreted by the gland-cells, and does not first become acid in the
stomach.

Such observations as have been made in order to ascertain whether
the border cells yield an acid reaction have not been successful.
Though the mass of evidence is very greatly in favour of the view that
the border cells are the origin of the acid of the juice, there are not
wanting those who deny it entirely. Contejean ^ observed, as had
previously been shown l:)y Langley,- that the stomach cells of the frog,
although they secrete acid, also secrete pepsin. But a more remarkable
statement is that the pylorus cells secrete an acid juice. This is so
much at variance with the results of the majority of investigations, that
it cannot be accepted as correct. If it were true, a conclusive proof
would be furnished against the view that the Ijorder cells originate the
acid.

As regards the functions of the different regions of the stomach, it
may be stated that the fundus and the greater curvature form in most
animals pepsin, hydrochloric acid, and other constituents of the gastric
juice. But considerable discussion has taken place as to the functional
importance of the pyloric region. That an extract can be made from
the pyloric region containing pepsin is generally agreed, but such an
extract, in comparison with one prepared from the rest of the stomach,
has very small digestive value. Langley,^ in one experiment on the
mucous membrane of the mole, found that if tlie digestive power of
the pyloric region be taken as 1, that of the fundus would be 73.
What then is the source of the pepsin that can be obtained from
the pyloric mucous membrane ? Is it pepsin formed by the gland
cells in the pyloric region, or is it absorbed pepsin that has
passed with the absorbed food into the mucous membrane of this
region ?

Wassmann '^' and v. Wittich * have held that the pepsin was merely
infiltrated pepsin, and Wassmann stated that it was removable by
repeated washing with water. On the other hand, Eljstein and
Griitzner^ found that washing the mucous membrane of the pylorus
causes but a very slow loss of pepsin. If, then, the cells of the mucous

^ " Contribxition a I'etufle de la physiologic de restoniac," Centralhl. f. Physiol.,
Leipzig u. Wieii, 1892.

- Proc. P,oy. Soc. London, 1881, No. 212.

^ " De digestione uonnuUa," Berolini, 1839.

'' "Ueber die Pepsinwirkimg der Pylorusdriison," Arch.f. el. ges. PJiysioI., Bonn, 1873,
Bd. vii.

'' "Ueber den Ort der Pepsinbildung in Magcn," ibid., 1872, Bd. vi.



FUNCTIONS OF DIFFERENT FORMS OF CEILS. 535

membrane absorb and fix pepsin, they fix it in a somewhat stable
combination. Such absorption would be comparal)le to that which, as
V. Wittich pointed out, fibrin exerts when placed in a glycerin solution
of pepsin, the fibrin rapidly aljsorl)ing the pepsin so as finally to render
the glycerin solution inert. The pepsin so absorbed can only be
recovered by treatment with hydrochloric acid and not by extraction
with water. Finally, Klemensiewicz ^ and, later, Heidenhain ^ have
isolated portions of the pyloric mucous membrane, and observed the
secretion thereljy obtained. But in Klemensiewicz's experiments the
secretion was so mixed with abnormal fluids, such as pus, that the
observations cannot be regarded as an index of the normal state of its
composition. In Heidenhain's observations this difficulty was avoided
by the adoption of antiseptic precautions. He obtained a secretion
alkaline in reaction, viscous in character, rich in pepsin and rennet
ferment. With hydrochloric acid Ol per cent, it digested fibrin very
energetically, and caused milk to clot in about a quarter of an hour.
Both Klemensiewdcz and Heidenhain insist on the strong proteolytic
powers of the secretion ; the former even states that it digests fibrin as
rapidly as the juice from the mucous membrane of the fundus. There
is then a certain amount of disparity between the results of extracting
the mucous membrane with various fluids, and testing the proteolytic
powers of the extracts and those obtained by observing the peptic
strength of the juice secreted by an isolated portion of the pyloric
region of the stomach. We must therefore ask which furnishes us with
the best criterion of the normal activity of the pyloric mucous
membrane ? By extracting with hydrochloric acid a large proportion of
the pepsin present in the mucous membrane can ultimately be removed.
But Klug ^ finds that, in order to obtain all the pepsin from the pyloric
mucous membrane, it is necessary to make at least three successive
extracts with hydrochloric acid, each one of the duration of twenty-four
hours. The first extract shows little or no peptic activity; the second and
third, marked activity. He ascribes the change of activity to the pro-
bability that the large amount of proteid present prevents the acid from
separating the pepsin from its proteid compounds. But this difference
is not found with the fundus, and it is somewhat difficult to understand
why it should be more easy to extract the pepsin by acid from the
fundus glands than the pyloric. We may regard it therefore as
probably true that repeated extracts furnish us with a considerable
amount of the pepsin obtainable. On the other hand, it may be asked
how far the juices secreted into artificially isolated portions of pyloric
mucous membrane are to be regarded as normal ? It seems that in
Heidenhain's case there was an absence of inflammatory conditions.
But it must be noticed that the operation performed involved very
considerable interference with the nerve supply to that portion of the
mucous membrane. The mucous membrane was probably, therefore, to
some degree in an abnormal condition. Nevertheless, the fact that
proteolytic powers were shown could not be explained by reason of
such an abnormal state; they must probably be indicative of normal
secretion. It seems impossible that any "infiltrated" pepsin could
produce the enduring effect in the secretion noticed by Heidenhain, and

1 Oj). cit. - 0}^ cit.

^ " Untorsucli. aus dem Gebiete der Magenverdauuiig, " Ungar. Arch. f. Med.,
Wiesbaden, 1894, Bd. iii.



536 MECHANISM OF SECRETION OF GASTRIC JUICE.

it may be regarded as established that the pyloric glands do secrete
pepsin.

The results of experiments that have been made to ascertain
whether pepsin or pepsinogen is contained in saline extracts of the
pyloric mucous membrane, lead to the conclusion that pepsinogen
may be present. The fact that the amount of pepsin obtainable from
the pyloric mucous membrane is increased rather than diminished ^ as
digestion advances is susceptible of one of two explanations. It may
be that during digestion the intracellular formation is more rapid than
the secretion, and thus an absolute increase in the pepsin contents of
the cells occurs. Or it may be that in course of absorption of certain
products of digestion by the pyloric mucous membrane, a certain
amount of pepsin becomes "infiltrated" in the membrane. At any
rate, there is something fundamentally different in this respect between
the secretion of pepsin at the pyloric end of the stomach and in
the fundus glands, for in the latter the amount of pepsin decreases
as digestion advances, whilst in the former there is an increase. Nor
is there any evident change in the histological appearance of the pyloric
cells corresponding to a secretory process. It is probable, as Langley
has suggested, tliat the precursor of pepsin (" mesostate," as it may con-
veniently be called) is not so highly specialised as in the fundus glands ;
or there may be a series of mesostates, the more highly developed
splitting off the enzyme earlier than the more lowly. The observations
of Klug, which are confirmatory of the much older observations of
Brliclse, that a series of hydrochloric acid extracts will continue to show
proteolytic powers, suggests that there are several mesostates of
different grades coexistent in the cell. It is, moreover, possible that
only in the most highly specialised mesostates does the condition of
secretory granules obtain. From all this it appears probable that the
formation of pepsin is a subsidiary function of the pyloric mucous
membrane, and that it yet remains to be discovered whether the cells
of the pyloric glands possess other more important functions.

The methods of obtaining gastric juice. — The older observers
obtained samples of gastric juice by causing animals to swallow hollow
perforated balls, containing pieces of sponge. In this way Eeaumur,^
Stevens,^ and Spallanzani ^ obtained a fluid which caused meat to
become digested, and which was marked by antiseptic properties.
Tiedemann and Gmehn^ made fasting animals swallow pebbles, which,
acting as mechanical irritants, permitted a certain quantity of gastric
juice to be secreted, and this was obtained by killing the animals shortly
afterwards.

Beaumont had under observation in 1822 a man who had a gun-shot
wound in the left side. There resulted from this a permanent fistula
into the stomach. A valve, formed of the mucous membrane, became
established over the opening, and on depressing this, introducing a
tube, and turning the man on his left side, a flow of gastric juice was
obtained.

^ See Gnitzner's chart (Fig. 44), in the section on the variations in composition of gastric
juice during digestion.

- "Sur la digestion," Hist. Acad. roy. d. sc. de (Parin), 1752.

" "De alimentorum concoctione," Edin., 1877.

* "Experiences sur la digestion de I'honime et de differentes especps d'animaiix,"
Geneve, 178.3.

^ "Die Verdauung nach Versuchen," 1826.



I NFL UENCE OF NER VO US S YSTEM. 5 3 7

Since this time many other cases of gastric fistula in the human subject
have been under observation.^ In 1842, Bassow- and Blondlot simultaneously
introduced the method of obtaining gastric juice by an artificial fistula in an
animal, and this method was further developed by Heidenhain,' who introduced
antiseptic precautions into the operation.

Heidenhain also succeeded in so developing Klemensiewicz's method of
isolating one portion of the stomach from the rest, that it was possible to keep
the animals under protracted observation in this condition. In making the
incisions for the operation, Heidenhain interfered as little as possible Avith
the more important blood vessels, but he apparently produced some disturb-
ance as far as the connections of the main nerves of the stomach were
concerned.

Pawlow's ■* method of isolating by operation a portion of the stomach,
retained the advantages of that of Heidenhain, while keeping unimpaired
the nerve distribution to the isolated portion.

The influence of the nervous system on gastric secretion. —

The stomach is suppHed with two sets of nerve-fibres, cerebro-spinal
and sympathetic. The vagi constitute the cerebro-spinal set, and branches
from the solar plexus the sympathetic. The fibres of the vagi are almost
entirely non-medullated in their course over the stomach. Plexuses
formed by these nerves lie between the muscular and in the submucous
coats. The nerve-fibres are distributed to the muscular tissue, to the
blood vessels, and to the mucous membrane, and filaments have been
traced to terminal arborisations between and in close contact with the



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 76 of 147)