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shown that many of the ferments of the alimentary canal have a
zymogen stage. Hammarsten,^ in 1872, pointed out that the gastric
glands of many animals contain rennet-zymogen, but do not contain
rennet-ferment. The zymogens of pepsin and trypsin were not

^ "Pepsin and Pep.sinogen," Journ. Physiol.. Cambridge and London, 18S6, vol. vii.
' Jalircsb. il, d. Fortschr. d. Thier-Chem., Wiesbaden, 1872.


described till some years later. Langiey ^ showed that the method of
separating pepsin from pepsinogen was applicable also to the rennin,
since rennet-ferment was destroyed by sodium carbonate, whilst reunet-
zymogen is affected much less powerfully. Hammarsten has also shown
that the amount of rennet-ferment that can be extracted from the
cardiac end of the stomach is proportionally much greater than that
obtainable from the pyloric mucous membrane. Griitzner ^ has shown
that in the gastric glands of the dog, the rennet-ferment diminishes m
amount during digestion, and that the amount of diminution runs
parallel to that of pepsin. It seems that where pepsin is greatest in
quantity, there also is rennet-ferment most abundant, and it seems
probable that the granules of the chief cells contain the zymogens both
of rennet-ferment and pepsin. We cannot say whether the granules are of
one kmd or whether there are separate forms of granules for the separate
ferments. But though in general the zymogen of the rennet-ferment,
and not the actual ferment, is existent in the gastric cells, yet in
some cases, e.g. the calf and sheej), the zymogen is presumably in a








1 1




^ — -r — i

1 — ^

— ^^f

1 1

r^ — 1

10 12 14 16 18 20 22 24 26 28 30 32

Fig. 44. — The figures at tlie abscissse on tlie base line refer to the
uixmber of hours elapsed since the last meal. The length of the
ordinates indicates the amount of pepsin yielded at any time. F is
the record of variation in the fundus mucous membrane, P of
variation in the pyloric mucous membrane. — After Griitzner.

much less stable condition, for a watery extract of the stomach of
these animals yields rennet-ferment in large quantities. As regards
the differentiation of the rennet-ferment from the proteolytic, they can
be separated from one another by chemical means, although we have
no morphological signs of their distinction. Hammarsten's method of
separating the two ferments chemically depends upon the fact that
the gradual addition of lead acetate precipitates the pepsin sooner than
the rennin.^

The variations in the amount and composition of gastric juice
during the course of digestion. — The amount of pepsin that can be
extracted from the mucous membrane has been estimated by Griitzner.*
He compared concurrently that obtained from the fundus with that
yielded Ijy the pyloric region. In the above chart (Fig. 44), which shows
the chief variation dui'ing the lapse of some hours after a meal, the most

^ "On the Destractlon of the Ferments of the Alimentary Canal," Journ. Physiol.,
Cambridge and London, 1882, vol. iii.

- Arch. f. d. ges. Physiol., Bonn, 1878, Bd. xvi.

" The conditions of formation of the hydrochloric acid of the gastric juice are treated
of in a preceding article (see pp. 351 et scq.).

■* Arch.f. d. ges. Physiol., Bonn, 1879, Bd. xx.




striking feature is the absence of coincidence between the pepsin con-
tents of the pyloric and the fundus region of the stomach.

In general, it may be pointed out that the maximal yield of pepsin
from the pyloric region is at the same interval after ingestion of food as
marks the minimal yield of pepsin from the fundus.

A great number of observations have been directed to estimating the
acidity of the contents of the stomach at different intervals after a meal
has been taken. G-astric juice commences to be secreted almost as soon
as suitable food enters the stomach. For a tune the acid juice merely
neutralises the alkalinity of the food and saliva, and the hydrochloric
acid combines with various food substances, so that free hydrochloric
acid does not occur till after an appreciable interval. Von den Velden ^
states that free hydrochloric acid
cannot be detected until three-
quarters of an hour after a meal
is taken. Kichet ^ states that in
the human stomach the acidity
gradually increases during diges-
tion, and that it is apparently
independent of the quantity of
fluid taken. Towards the end
of digestion he finds that the
total acidity of the stomach con-
tents may be further increased,
but this is to be referred to the
production of organic acids by
the decomposition of the food.
He also points out that the feebler
the activity of the juice, the
greater the amount of organic
acid liberated. Chischin's ^ observations give precise details of the course
of digestion with different foods. The annexed diagram (Fig. 45) shows
the course of the production of hydrochloric acid in an isolated portion
of the fundus, when the animal was fed with mixed food, comprising
milk, meat, and bread. The animal did not undergo the " psychical "
stimulation of the food, or the maximal percentage of hydrochloric acid
would probably have been in the first hour, instead of in the second or
third. If meat alone be given to such an animal under similar conditions,
the maximal acidity occurs in the first hour. With mixed food the digest-
ive power averages 3-5 mm. (Mette's method of estimation by columns
■of coagulated egg-white) ; * with simply meat food, about 4 mm. With
bread alone as food, the duration of secretion was found to be more
protracted, but the digestive strength was much greater, varying between
5-22 mm. and 7-56 mm. The digestive power was very marked in the
first hour, increased further in the second hour, and remained high both
in the third and fourth hours. With milk, the course of secretion is
much more irregular. The digestive power is moderately high at first,
but sinks, after the first hour, about one-half. It remains at this
strength for the third and fourth hours, but in the fifth hour increases
again to the original strength, and may, in the sixth hour, even go

1 "Zur Lelire von der Wirkung des Mundspeicliels im Mageu," Ztsclir. /. 2jhysiol.
Cliem., Strassburg, 1879, vol. iii.

- Oih cit. ^ Op. cit. * For Mette's method, see p. 325.

VOL. I.— 35

1 2 3 4 5 6 7

Time in hours after food is tal<en

Fig. 45. — Chart showing acidity of gastric
juice after feeding with mixed food (300
c.c. milk, 50 grnis. meat, and 50 grnis.
white bread). The animal was not sub-
jected to the "psychical stimulation" of
the food.


beyond this. In another series of experiments the animals were fed
with peptone (Chapoteanx). This, according to Chischin, was equivalent
to reviewing the later stages of digestion, from the time when peptone
began to be formed in any quantity in the stomach. The noticeable
point about the results in these last cases is, that there is presented a
great contrast to feeding with such a primary proteid as egg-albumin.
XVith peptone, the juice becomes secreted in large quantities at once,
its acidity is high, and its digestive power well marked.

It is obvious, therefore, that the nature of the food has an important
influence on the course and nature of the secretion. This has been
drawn attention to by Khigine,^ who classes the different foods
mentioned above in different orders. He has also pointed out that the
amount of juice secreted is not necessarily proportional to its acidity
or its digestive power. These, again, are not necessarily proportional
to each other, as is shown in the case of bread as food, when a low
acidity in the secreted juice is shown, but a high degree of peptic
power ; whereas with milk a high degree of acidity is shown, but a much
lower degree of digestive power. Finally, the duration of the digestive
process is out of all relation to the strength of the secreted juice. It is
impossible, then, to draw up any regular scheme of the course of digestion,
except so far as specific foods are concerned, observations based upon the
course of digestion of foods mixed in arbitrary proportions being of but
little value.

The Mechanism of Pancreatic Secretion.

The histological appearances of the different secretory condi-
tions of the pancreas. — The pancreas consists of secretory alveoli,
between which are here and there seen masses of cells of a different
character, and having no connection with the proper secretory channels
of the gland. These masses of cells are presumably not connected with
the ordinary processes of the secretion of a digestive juice, and the follow-
ing account will therefore be confined to the typical secretory alveoli.

If a small portion of the pancreas of an animal be examined in the
living state, it will be found to consist of many secretory alveoli, and
these secretory alveoli of cells contain numbers of discrete granules.
It is generally found that whatever digestive stage the animal is in, there
exists an outer zone in the alveolus free from granules. This is not,
however, invariably the case. Ordinary stains, such as h hematoxylin
and carmine, are found to colour this outer zone more deeply than the
rest. This is in conformity with the usual rule, that such stains do not
deeply colour the secretory granules of cells, or the substance formed by
their breaking down. If the cells are macerated for a few days in
neutral ammonium chromate, a radial fibrillation is revealed ^ in this
outer zone. The addition of water to the fresh gland causes the
granules to disappear, and dilute alkalies produce this result even more
rapidly. Acids, either mineral or organic, cause the distinction between
the two zones to be lost, the whole cell becoming clear. By hardening
the gland in solutions of osmic acid, or in the vapour of osmic acid, the
granules may be x^reserved.

^ " Etudes sur I'excitabilite secretoirc specifique de la m\iqueuse du canal digestif"
Arch, de sc. bioL, St. Petersbourg, 1895, vol. iii. p. 5.

^ Heidenhain, Hermann's "Handbnch," Bd. v. Abtb. 4.


Although, in the resting condition of the gland, an outer boi'der free
from granules is evident, this is still more manifest in the exhausted
condition. The granules may then be so reduced in number as to form
small aggregations at the luminal borders only of the cells.

As is the case in the stomach, there is reason to believe that the
granules are concerned with the specific secretion of the gland, the
amount of granules determining the activity of an extract.

The above described changes in the cells were first observed in the
living pancreas of the rabbit by Kiihne and Sheridan Lea.^

Methods of obtaining pancreatic juice. — The methods that have been
adopted to procure a supply of pancreatic juice involve one of the folloAving
procedures — (a) Fixing a cannula into the duct of Wirsung ; (Ji) opening the
duct and connecting it with the body wall ; (c) cutting out a piece of the
intestine in which the pancreatic duct opens, and fixing this to the body

C. Bernard ^ adopted the j&rst method, fixing a silver cannula into the duct.
Heidenhain ^ introduced antiseptic precautions into the operation. He made
an incision in the linea alba midway between the xiphoid process and the
umbilicus. The duodenum was drawn out through the opening and the duct
carefully sought for. This being found, into it was tied a glass cannula
of about 6-18 cms. in length. Around the intestine were placed two
temporary ligatures, keeping the gut closely applied to the body wall. The
opening was found to gradually close, allowing simply the cannula to pass
through. The second method was adopted by Ludwig with Weinmann,'^ and
Bernstein.^ They found and opened the duct and inserted a piece of lead wire,
on the one hand, towards the papilla pancreatica in the duodenum, the other
end passing up to the gland substance. This wire did not fill the lumen, and
thus the flow was still permitted. The third method, which is due to Heidenhain
and adopted for p)ermanent fistulee, consists in resecting the small portion of the
intestine which contains the papilla pancreatica, and joining the ends of the
main gut above and below. The piece of intestine is slit up, the mesenteric
surface is attached to the body wall, and thus the juice can be obtained.
Pawlow varied this method by not resecting the whole tube of the intestine.
He cut out a quadrangular piece, including the pancreatic papilla, and ligatured
this into the body Avail.

By these different methods natural pancreatic juice may be obtained.
After a time the juice becomes somewhat altered ; it retains, however, its
ferment activity in a marked manner throughout.

The influence of the nervous system upon pancreatic secretion.

— Our knowledge has lately been considerably extended in respect of
the precise influence of nervous impulses upon pancreatic secretion.
The following statements summarise our chief knowledge up to the
most recent researches upon the subject.^

1. After division of the nerves, proceeding to the gland, secretion is set
up and apparently increases. This was affirmed by Bernstein.'^

2. Secretion can be set up by stimulation of the medulla oblongata,
or, if already in progress, can be increased.^

3. The medulla oblongata must not be regarded as exclusively the

^ Verhandl. d. natitrh.-med. Vcr. zu Heidelberg, IST.F., Bd. i.

" ' ' Memoire sur le pancreas et sur le role du sue pancr^atique," Compt. rend. Acad. d. sc.
Paris, 1856.

^ Hermann's " Handbucli," Bd. v. ** Ztschr. f. rat. Med., Bd. iii.

^ Ber. d. k. sacks. Gesellsch. d. IVissensch., Leipzig, 1869.

^ Cf. Heidenhain, Hermann's "Handbucli," Bd. v. Abth. 4. " Op. cit.

® Heidenhain, Arch, f, d. gcs. Physiol., Bonn, 1875.


centre for pancreatic secretion, as, after its separation from the cervical
spinal cord, the secretory process can continue, although with diminished

4. The nerves proceeding to the pancreas do not seem to have the
same direct influence upon the secretion that the nerves to the salivary
glands possess.

5. Stimulation of the central end of the divided vagus, according to
Bernstein,^ or of sensory nerves in general {e.g. cutaneous), according to
Afanassiew and Pawlow,^ may inhibit the secretion, provided the pan-
creatic nerves are intact. This, Heidenhain regards as due to vascular

Pawlow^ found that the administration of atropine stopped the
secretion frequently, but not m all animals {e.g. in dogs but not in
rabbits), and Heidenham observed that the admmistration of pilocarpine
caused a sluggish secretion of a concentrated juice.

The later experiments of Pawlow and the St. Petersburg school have
greatly amplified our knowledge of the nervous influence. In Pawlow's
further researches he observed the effects of nerve stimulation upon dogs
prepared for experiment in two different ways. In the first case the
dog had a permanent pancreatic fistula prepared, one vagus in the neck
was also divided. The stimulation of the peripheral stump of the vagus
was performed some five days after the section, at a time when certain
fibres in the vagus had degenerated. In the second case the vagus was
cut through in the neck, and after three or four days the anmial was
prepared for experiment by the performance of tracheotomy, section of
the spinal cord just below the medulla oblongata, and the preparation of
a fresh pancreatic fistula. In both these cases stimulation of the peri-
pheral end of the vagus causes secretion from the pancreas. Moreover,
stimulation of the intact vagus also produces this result, and even if
neither vagus is divided a more or less pronounced secretion ensues.
Certain differences are observable, however, between the general effects in
the two cases. In the first case more secretion was produced, this being
comparatively watery in character and greatest in amount at the
commencement of stimulation. These differences are probably accounted
for by the general low blood pressure in the second case. The pressure
of the secretion was found by Pawlow to l^e lower than the corresponding
blood pressure, and it was noted that vagus stimulation in one case still
caused a secretion, although the blood pressure was reduced by bleeding
practically to nil. Frequently the secretion would end with the lowering
of the blood pressure, but nevertheless the one experiment is sufficient
to establish the independence of the secretion of the blood pressure.
The action of atropine is to cause a marked influence on the effects
of nerve stimulation, though complete cessation of the secretion is not
produced. Eeflex effects can be produced on the secretion, which do not
correspond to the effects upon the blood vessels. Stimulation of the
central stump of the lingual or of the vagus nerve will produce such reflex
effects. If, at the commencement of the experiment, either no secretion
or a slight secretion occurs, with the first stimulation of sensory nerves
either a commencement or an increase of tlie secretion results. After
the stimulation ceases tliis lessens. If after the first stimulation the

' Bar. d. Ic. sacks. Gcsellsch. d. IVisscnsch., Leipzig, 1869.
- Arch. f. d. r/fis. Physiol., Bonn, 1878, Bd. xvi.
" Arch. f. Physiol., Leipzig, 1893, Supp. Bd.


secretion is still fairly marked, a further stimulation will result in
inhibition of the secretion, which inhibition ends with the stimulation
provoking it. The spontaneous secretion that is sometimes observed
before the experiment begins, is stopped by cutting both vagi, and is
therefore due to impulses proceeding from the upper portion of the
cervical spinal cord or the medulla oblongata. Pawlow also points out
the importance of the circulation in general for the secretion. A brief
stoppage of the blood stream caused a cessation of the flow, and an
ansemic condition of the gland resulting from reflex nervous influence
caused a similar cessation. The latent period relapsing before the
secretion resulting from stimulation becomes obvious, is, according to
Pawlow, two to three minutes, but later observers such as Mette ^ and
Kudrewetzky ^ regard it as somewhat longer, namely, from four to six
minutes. Mette in addition found that, though previous observers
(Lewaschew, Heidenhain) had stated that the proteolytic ferment failed
in the pancreatic juice of dogs which had fasted five or six days, yet it
was continuously obtainable by stimulation of the vagus. Gottliel) ^
confirms the old observation, that stimulation of the divided vagus at the
central end causes inhibition of the secretion, and he refers this result to
general spasm of the abdominal blood vessels. Another contribution to
the study of the inhibitory influences on the pancreatic secretion has
recently been made by Popielski.* It had been previously noticed by
Mette and Kudrewetzky that the secretion caused by stimulating one
vagus could frequently l)e stopped by stimulating the other vagus.
Hence it was inferred that antagonistic fibres passed in these nerves.
Stimulation of such fibres may bring about sometimes a lengthened
latent period, sometimes total inhibition of the flow. Mette regarded
this as due to the existence of vaso-constrictor fibres, Kudrewetzky
to the presence of specific fibres inhibiting the secretion. Popielski
endeavoured to elucidate this point. He found that a secretion evoked
by peripheral stimulation of the vagus could later, by a repetition of
the stimulation of the same nerve, be interrupted. The interruption
started some seven seconds after the stimulation commenced, and
lasted about the same interval beyond the cessation of stimulation.
This inhibition also follows from stimulation of the other vagus, as
previously observed, and is best shown when the exciting current
is not too strong. The branch of the vagus which lies behind the
oesophagus in the thoracic cavity is that concerned with changes in
the secretory activity of the pancreas. Dolinski^ had previously
observed that the introduction of acids into the duodenum produces
a flow of pancreatic juice (see next section). Popielski made use of
this fact to see how far the secretion thus excited could be inhibited
by nerve stimulation. He found that a secretion so produced
was inhibited with perfect regularity by stimulation of the vagus.
Stimulation of the vagus, after secretion evoked by pilocarpine, pro-
duced the same result. Popielski points out that there are three
ways in which inhibition of the flow of pancreatic juice can be brought
about —

1. By stimulation of vaso-constrictor fibres.

' Arcli.f. Physiol., Leipzig, 1894, Supp. Bd. " Ibid., 1894.

■* Arcli.f. exper. Path. u. PharmakoJ., Leipzig, 1895, Bd. xxxiii.
•* Centralhl. f. Physiol., Leipzig u. "Wien, 1896, Bd. x.
^ Arch, de sc, biol,, St. P^tersbourg, 1895, vol. iii.


2. By constriction of the lumen of the duct, resulting from contrac-
tion of its smooth muscle.

3. By action of special nerve-fibres inhibiting secretion.

The first hypothesis is improbable, since stimulation of the splanchnics
does not cause the same cessation ; and, moreover, there is reason to doubt
the existence of vaso-constrictor fibres in the vagus.^

The second h^^pothesis will not hold, when it is considered that
physostigmine produces duct constriction, but at the same time increases
the secretion.

Before examining in detail the third supposition, Popielski endeavoured
to see how far special secretory fibres can be anatomically isolated. If
the larger branches of the vagi lying on the stomach, or those branches
which pass towards the liver, be divided, stimulation of the vagus has the
same influence upon pancreatic secretion. The impulses pass therefore
along some of the finer nerve branches running in the subserous coat
towards the pyloric region of the stomach. If the duodenum be cut
through near the pylorus, stimulation of the vagus has no effect. If
the duodenum be cut across lower down, the vagus effect is apparent.
Stimulation of the lower cut edge of the duodenum in the first case
provokes secretion, and if the main mass of nerves passing with the vein
into the gland be stimulated (especially those lying at the upper side of
the vein), a secretion is evoked without marked latent period, and
uniform in character. This secretion is inhibited by the simultaneous
stimulation of the vagus in the thoracic cavity. The inhibition comes
about, then, either by impulses passing along nerve-fibres to the gland-
ceUs, or affectmg some nerve-centre. Popielski finds that if the vagi
and sympathetic nerves be cut, a reflex secretion is still evoked by
placing hydrochloric acid in the duodenum. The reflex centre, he thinks,
then, must be in the abdominal cavity. He considers it probable that
such a centre exists in the region of the pylorus, since, if the duodenum
be cut through near the pylorus, the introduction of hydrochloric acid is
then without effect. If the pylorus be separated with the duodenum,
hydrochloric acid will then, however, have the usual effect of causing
pancreatic secretion. Popielski considers, however, that such a reflex
centre is not furnished by the semilunar ganglion.

If these observations are correct, we can assume the existence of
secretory and mhibitory nerve-fibres, both running in the vagi, and it
seems probable, from the differences of latent period which result from
stimulation in different regions, that the inhibitory impulses passing
along the vagus do not act directly on the cells of the gland, but on
some centre which has a controlling influence on the process of secretion.
Popielski's reasons for regarding the semilunar ganglion as probably not
furnishing such a centre, seem insufficient. The fact that Bernard found
an increased secretion after extirpating this, can be explained, on the
analogy of the salivary gland, as a paralytic secretion. There is some
e\"idence that the inferior mesenteric ganglion may also act as a centre
for reflex action, and if so, it seems less improbable that a similar reflex
centre for the pancreatic secretory processes may be referred to the
semilunar ganglion. Should such a centre exist, it is undoubtedly
subject to influences proceeding from the higher centres by means of the

Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 78 of 147)