centres in the ganglia of the plexuses of the stomach and intestine have an influence on both blood-vessels and secretion. Such a theory would require very forcible backing up before it could be regarded as tenable. All recent research goes to prove the relatively small importance of peripheral centres for the carrying out of reflex actions.

2. THE STRUCTURE OF AND CHANGES IN THE CELLS THAT SECRETE GASTRIC JUICE

Two kinds of glands are distinguished which differ from one another in the character of their enclosed cells, and in the nature of their secretion. The pyloric glands are so called because they are found most numerously in the pyloric region; they are distinguished by the large size and depth of the gland mouth or duct as compared with the tubules that open into it. The duct is lined by columnar cells continuous with and similar to the columnar epithelium covering the general internal surface of the stomach; the tubules are lined with shorter and more cubical cells, which are uniformly granular throughout. The cardiac glands (fundus glands of Heidenhain) are so called because they occur most numerously in the cardiac half of the stomach. Their duct is short, their tubules, in proportion, long. The latter are filled with polyhedral cells, only a small lumen being left; they are more coarsely granular than the corresponding cells of the pyloric glands. These cells were called principal cells by Heidenhain,' adelomorphic cells by Rollett,2 and central cells on account of their position. Between them and the basement membrane of the tubule are other cells of a different nature called parietal cells (Heidenhain), delomorphic cells (Rollett), or oxyntic cells (Langley).3 They are most numerous in the more superficial portions of the tubules. Their granular appearance is due to a close and uniform intercellular network (Klein). They are readily stained by many colouring agents, especially aniline blue.

4

The changes that occur in these different cells on secretion have been worked at by Heidenhain, Ebstein," and Langley.

The following is in brief the substance of Langley's observations:The use of osmic acid is to be much recommended for studying these conditions, as hardening reagents like alcohol cause the granules to become swollen and indistinct.

The central cells exhibit changes similar to those already described

1 Arch. f. mikr. Anat. vi. 368.

2 Centralbl. med. Wiss. 1870, Nos. 21 and 22.

3 Journ. of Physiol. ii. and iii. (ögùs=acid). They were formerly called peptic cells,

a term that must now be discarded.

4 Stricker's Handbuch, 1871.

5 Arch. f. mikr. Anat. vi.

as occurring in the salivary glands. Before secretion they are 'loaded' with granules; during secretion they discharge their granules, those that remain being chiefly situated near the lumen, leaving in each cell a clear outer zone (see fig. 84).

The cells of the pyloric glands undergo similar changes. In both these cells and the central cells of the cardiac glands some substance

readily precipitable by alcohol makes its appearance during discharge, as this reagent then renders the cells turbid.

The oxyntic cells undergo merely a change of size during digestion, being at first somewhat enlarged and then shrinking to less than their original volume (Heidenhain).

We have in the granules of the central cells another instance of a zymogen or ferment-precursor. It is the precursor of pepsin, and is called pepsinogen. The parietal cells are those which secrete the hydrochloric acid. The evidence upon

which this statement rests is the following: Heidenhain by means of a surgical operation, performed antiseptically, succeeded in making in one dog a cul-de-sac of the fundus, in another of the pyloric region of the stomach; the former secreted a juice containing both acid and pepsin; the latter, parietal cells being absent, FIG. 84. -A Cardiac Gland of simple form secreted a viscid alkaline juice containing

from the Bat's Stomach. Osmic acid preparation (Langley). c, columnar epithelium of the surface; n, neck of the gland, with central and parietal cells; f, base or fundus, occupied only by principal or central cells, which exhibit the granules accumulated towards the lumen of the gland.

pepsin.

Brücke showed that the acidity of the glands is greatest near their mouth; here also the parietal cells are most abundant; and no doubt the acid is quickly expelled from the glands. Cl. Bernard showed this by his well-known experiment of injecting potassium ferrocyanide in one vein of an animal, and lactate of iron into another. These substances in presence of free acid strike a blue colour, and he found only the surface of the mucous membrane of the stomach was blue. In the frog there is a well-marked separation of two regions: the oesophageal region, free from parietal cells, secretes an alkaline juice; the stomach itself, which contains the parietal cells, an acid juice (Langley).

Thus, although there can be but little doubt that the central cells secrete pepsin, the argument that the parietal cells secrete acid is at present one of exclusion only.

The rennet-ferment (rennin or chymosin) appears to be formed by the same cells that manufacture pepsin. Hammarsten 1 and Langley 2 obtained evidence of the existence of a zymogen of rennin analogous to that of pepsin or ptyalin; a weak alkaline extract of the mucous membrane contains no rennet; a weak acid extract contains rennet, and causes clotting in milk, even if the extract be made alkaline. A weak acid is generally found effective in converting a zymogen into a zyme or ferment.

The secreting cells of the stomach, like secreting cells universally, select certain materials from the lymph which bathes them; these materials are worked up by the protoplasmic activity of the cell into the secretion which is then discharged by the cell into the lumen of the gland of which it forms part. The most important substance in a digestive secretion is the ferment; in the case of the gastric juice this is pepsin; we can trace an intermediate step in the process by the visible presence of its precursor, pepsinogen. But another equally important material in the juice is the acid, for pepsin acts only in acid media. We have now, therefore, to consider a little more fully the differences between pepsin and pepsinogen, and, secondly, the important but puzzling problem of the formation of a free acid from the alkaline blood or lymph.

Pepsin and pepsinogen.-The following research was carried out by Langley and Edkins. Their object was to discover a method of determining the relative amounts of pepsin and pepsinogen in any given fluid, and thence to determine whether both exist in the gastric glands. The following two methods were found to give approximate results :

(1) The power of sodium carbonate to destroy pepsin is much greater than its power to destroy pepsinogen. Thus if equal volumes of neutralised acid extract of gastric mucous membrane and 1 per cent. sodium carbonate solution be mixed, to 1 of the pepsin is destroyed in fifteen seconds, and it is unable to digest such a proteid as fibrin.

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(2) The power of carbonic acid to destroy pepsinogen is greater than its power to destroy pepsin. If an aqueous extract of a frog's œsophagus be taken, and a stream of the gas passed through it for half an hour, 18 to 5 of the digestive power of the fluid is destroyed; while if an aqueous extract be warmed with dilute acid in the first instance, to convert the pepsinogen into pepsin, and it is then neutralised and the gas passed through it, there is little or no loss of digestive power. The passage of carbonic acid through the extracts throws down a precipitate of a globulin; but pepsinogen, which is thus probably a globulin, is not carried down unaltered, since a solution of the precipitate in dilute hydrochloric acid has little or no digestive power. Pepsinogen and pepsin are both destroyed at 54° to 57°, the temperature at which the globulin is coagulated. 2 Journ. of Physiol. iii. 287.

1 Maly's Jahresb. 1872, p. 123.

3 Ibid. vii. 371.

The destruction of pepsinogen by carbonic acid is increased by the presence of a small amount of neutral salt, and diminished by small amounts of peptone. The gases oxygen and carbonic oxide have no effect on either pepsinogen or pepsin.

On applying the above methods to the œsophageal glands of the frog, it was found that little or no pepsin is present in the cells themselves. The conversion of pepsinogen into pepsin that occurs when the secretion leaves the cells is, no doubt, the same chemical change as that produced by the action of a dilute acid on the zymogen.

1

The formation of hydrochloric acid.-There is at present no thoroughly satisfactory theory to account for the presence of free hydrochloric acid in the gastric juice. Foster suggests that it may be formed by the decomposition of some highly complex and unstable chlorine compound formed in the cell by union of organic substances with the chlorine of sodium chloride. Most other observers have considered that sodium chloride is a more direct source of the acid; but sodium chloride is, as Foster points out, an exceedingly stable substance, and carbonic acid, the only free acid in the blood, is a weak acid. The terms weak and strong as applied to acids are, however, misleading. So-called weak acids are, by what is termed 'mass influence,' able to unite with bases, displacing acids of greater avidity.' Thus the formation of free hydrochloric acid from sodium chloride and carbonic acid is not only a possible, but probably the correct explanation of the phenomenon (Bunge, Physiol. Chem.' p. 161). Ralfe attributes the production of the acid to the passage of electric currents through the mucous membrane, causing a reaction between sodium bicarbonate and sodium chloride, thus: NaHCO,+ NaCl = Na„CO2+ HCl, but there are no valid grounds for supposing that such currents exist. It appears to me more probable that it is lactic acid which is chiefly instrumental in the decomposition of sodium chloride. Lactic acid is generally found in the stomach during a meal, especially if the meal contains carbohydrates; fermentative changes in these produce the lactic acid, which reacting with the sodium chloride produces sodium lactate and hydrochloric acid. This view was first promulgated by Maly. Lactic acid certainly will decompose sodium chloride in this way in cold dilute solutions. Drechsel has discovered that the lactates in the blood are increased from 0.01 to 0.02 per cent, during digestion; a fact that supports Maly's view of the case. The great difficulty, however, in accepting Maly's theory is that carbohydrates are not always present in the food, and that a flow of acid from the gastric glands can be excited by distilled water or mechanical irritation. What, then, is the source of the lactic acid under those circumstances? This objection is met by Landwehr3 by the following ingenious theory, in which animal gum (p. 480) plays an important part: the lumen of the gastric glands is always more or less filled with mucus; when the glands are stimulated a ferment is produced which decomposes the mucin, forming lactic acid from its carbohydrate constituent (animal gum); this acid reacting on sodium chloride produces free hydrochloric acid and sodium lactate: the former is poured into the stomach; the latter is absorbed by the blood. If it be admitted that sodium chloride is a direct source of hydrochloric acid, Landwehr's theory of the modus operandi

Text-book, 5th edit. p. 419.

2 Sitzungs. d. Wien. Akad. vol. lxix. 1874; also vol. lxxvi. In the latter paper & further suggestion is made, viz. the acid originates by the interaction of the sodium chloride and the sodium dihydrogen phosphate of the blood.

5 Chem. Centralbl. 1886, p. 484; Pflüger's Archiv, xl. 21.

appears to be a satisfactory one. It is, however, possible that the sugar of the blood and lymph is the real source of the acid.

2

An attempt to solve the question was made by Külz'; he administered bromides and iodides, and then sought for free hydrobromic or hydriodic acid respectively in the gastric juice, and found it. As Drechsel points out, however, the decomposition might have been effected by the hydrochloric acid of the juice, and not by the metabolic activity of secreting cells. If chlorides are not given in the food, hydrochloric acid disappears from the gastric juice after a time (Cahn 3). It is found that as the acidity of the gastric juice increases, that of the urine diminishes. This is not because of any diminution of free acid in urine-as urine contains no free acid-but because the amount of the base liberated by the formation of the gastric acid is increased, and passes into the urine. If sodium lactate is produced it no doubt is changed into sodium carbonate, which passing into the urine tends to render it alkaline.

3. COMPOSITION OF GASTRIC JUICE

The methods of obtaining gastric juice that have been adopted are the following:

Spallanzani fed birds on pieces of sponge to which a piece of string was attached; after the sponge had remained in the stomach for a sufficient length of time to absorb the juice, it was pulled up by means of the string.

Since then gastric juice has been obtained from cases of gastric fistulæ both in men and animals. The first case carefully observed in a human being was that of Alexis St. Martin; the first artificial gastric fistula in dogs was made by Blondlot; 5 Bardeleben, Bidder and Schmidt, Bernard, Holmgren,9 Panum, 10 and many others have since then performed similar experiments.

7

8

6

For the investigation of the action of the gastric juice, it has been found that artificial gastric juice acts in the same way as the genuine article, and it is much easier to obtain. Schwann was the first to make an artificial juice, by extracting the mucous membrane of the stomach of a recently killed dog with 0-2 per cent. hydrochloric acid; v. Wittich was the first to make a glycerin extract of the mucous membrane. The mucous membrane must be allowed to stand twenty-four hours before the extract is made, or treated with a little dilute hydrochloric or acetic acid, or with solution of sodium chloride.11 By either of these means

1 Zeit. Biol. xxiii. 460.

2 Ibid. xxv. 396.

3 Zeit. physiol. Chem. x. 522.

4 Versuch. über das Verdauungsgeschäft, übers. von Michaelis, Leipzig, 1785. 5 Blondlot, Traité analytique de la digestion, Paris, 1843.

6 Arch. f. physiol. Heilk. 1849, vol. viii.

7 Die Verdauungsäfte und der Stoffwechsel, Mitau and Leipzig, 1852.

8 Bernard, Leçons de physiol. expérimentale, Paris, 1856.

9 Virchow-Hirsch, Jahresb. 1869, p. 103.

10 Ibid. 1879, p. 99.

11 Grützner, Neue Unters. ü. d. Bildung des Pepsin, Breslau, 1875.