Principles of General Physiology

Each of these factors requires a little more detail. In the following description the state of affairs as fully developed in the case of one of the higher vertebrates, man or the dog, is taken as typical ; in lower animals, vertebrate and invertebrate, various simplifications are to be found, as well as special additions for particular purposes. If the small intestine is cut out of an animal such as the rabbit, cat, or dog, and immersed in warm, oxygenated Ringer's solution, or better, in Ringer-Tyrode's solution, it is seen to exhibit a series of rhythmic contractions, which travel as

waves along the muscular coats. But another kind of movement can be produced by mechanical stimulation, such as that which the presence of food would afford. The nature of this movement was demonstrated by Bayliss and Starling (1899) in the intestine in situ, but separated from any connection with the central nervous system. It can also be obtained in the excised gut, under favourable conditions, and most readily in the colon of the rabbit. A gentle pinch at any spot causes a cessation of the rhythmic contractions in the region just below the place excited, together with a diminution of the state of moderate tonic contraction in which the intestinal muscle normally exists, upon which the rhythmic contractions are superposed. The word, " below," of course, refers to the normal direction of the movement of the contents of the intestine, and would perhaps better be called, "in front of." Coincidently with this relaxation in front of the point excited, there is an increased tonic contraction, with greater vigour of rhythmic movements, above, or behind the place excited ; these facts are illustrated by Fig. 95. To this phenomenon, which is common to the alimentary canal from the lower part of the esophagus to the rectum, in a more or less well-marked manner, we gave the name of " The Law of the Intestine." It is clear that it is what would

FIG. 95. THE LAW OF THE INTESTINE. — Contractions of the jejunum traced by a balloon in the lumen. At 1, pinched gently about an inch above the balloon. Immediate inhibition of rhythmic contractions below, with relaxation of tone. At 2, while still quiescent, a gentle pinch about half an inch below the balloon. After some six seconds sudden recovery of tone, with series of strong rhythmic contractions. At 3, similar pinch during normal contractions. Greatly increased strength of contractions.

happen if the intestine were distended at any spot by the presence of food, and that it would result in the moving on of the contents. In fact, a lump of cotton wool smeared with soft soap and inserted into the front end of a loop of rabbit's intestine (the colon works best), immersed in warm saline, is gradually passed on and escapes at the lower or posterior end. This seems to be a complex act for a muscular mass to perform apart from the central nervous system, but we must remember what there is in the wall of the gut. All along, we have two muscular coats, one arranged in a circular manner, the other in a longitudinal direction ; in some places, as in the stomach, additional layers are provided. Between the two coats there is what may be called a peripheral nervous system, a plexus of nerve cells and fibres, and from this there proceed nerves to the muscular coats. This nerve centre is known as " Auerbach's," or the myenteric, plexus. There is also another plexus, Meissner's, situated between the mucous membrane and the inner, circular, muscular coat. Nerves pass between the two plexuses and to muscles and mucous membrane. The reflex, which we called the "law of the intestine," requires for its manifestation the presence of Auerbach's plexus, but whether Meissner's is also necessary is not known. Nor can it be said whether the afferent impulses for the reflex come from sensory nerve endings in the wall of the gut, or whether the reflex ia

brought about by direct action on the nerve plexus. Cannon (191L') suggests that a better name for the local reflex in question would be the " mventei ic reflex," and the name has the advantage of being applicable to the whole alimentary canal. It seems clear, however, that some further regulation of the passage of food is required to prevent its being hurried along too rapidly ; even a means of sending it backwards and forwards. The muscular contractions causing movement onwards are generally known as "peristalsis" and those in the opposite direct inn, " antiperistalsis," but Cannon (1912) suggests, as a better terminology, the name " diastalsis " for the forward moving wave, controlled by the myenteric reflex and preceded by inhibition ; and " ana- and cata-stalsis " for the rhythmic waves of upward or downward movement, which are present independently of the myenteric reflex and not preceded by a wave of inhibition. These movements take place when the myenteric reflex is put out of action, as it can be by the influence of the central nervous system, as we shall now see.

There are two great nerves which control nearly the whole of the alimentary canal ; the vagus, which is the ancestral motor nerve for the whole of the gut, except the two extreme ends; even in the higher mammals it continues to act as motor nerve to the large intestine, remarkable as it may seem that a cranial nerve should have so posterior a distribution. Gaskell, in fact (1908, pp. 446-404), draws interesting conclusions as to the origin of vertebrates from the innervation of the alimentary canal.

Eduard Weber (1846) in his classical article in which he describes the discovery of the inhibitory action of the vagus nerve on the heart, also (p. 49) describes a remnrk;il>le died of the same nerve in the -Tench, where it produces a quick contraction of the intestinal muscle, "like skeletal muscle." The second great nerve supply is from the sympathetic system and contained in the splanchnic nerves. This is inhibitory. In Fig. 9G a tracing is given which shows how the rhythmic contractions are stopped and the tonus abolished when this nerve is excited. It is, as a rule, impossible to obtain the myenteric reflex unless the splanchnic nerves are cut, owing to the inhibitory control they have over its manifestation.

A curious fact in connection with the vagus is that its motor effect on the small intestine is preceded by an inhibitory one, and that the motor effect is not shown until after the nerve has been subjected to a series of periods of excitation. The tracing given in Fig. 97 is the result of the ninth of such a series, the first five of which showed no motor action. The more posterior part of the large intestine has its motor nerve supply from the pelvic visceral, or autonomic, nerves.

The best means of investigating the normal movements of the alimentary canal in digestion is that introduced by Cannon (1897 and 1902). The animal, or man, is given bismuth subnitrate, an insoluble, inert powder, mixed with the food ; by this means the contents of the alimentary canal are made opaque to the Rontgen rays and their shadows can be watched on the fluorescent screen. It has been made out that the food, having arrived into a particular section, say the stomach, is imprisoned therein for a time by closure of the sphincters. During this imprisonment it is thoroughly churned, backwards and forwards, until the enzymes have had time for their work, and the products of their activity, if absorbed in this part, have been taken into the blood and lymph. The proee-.-, of churning, whose mechanism can be observed best in the small intestine, <!<>e> not consist in a true antiperistalsis, preceded by a wave of inhibition, but by a series of local contractions dividing the contents into separate masses at different places in turn and thus pushing them upwards and downwards.

It has been shown by Serdjukov (see Pavlov, 1901, p. 187) that the pyloric sphincter of the stomach opens at intervals to allow a portion of the contents to escape into the duodenum ; as soon as acid is present therein, the pylorus closes by a nervous reflex, so that only a small amount of food is allowed to enter the duodenum at pne time. These movements of churning and so on appear to be mainly controlled from the central nervous system and are at intervals interrupted by a myenteric reflex, which carries the food onwards.

For further details the reader is referred to the monograph by Cannon (1911). FIG. 96. EFFECT ON THE INTESTINE OF STIMULATION OF THE SPLANCHNIC NERVES. — Cessation of contractions and relaxation of tone. An interesting point with reference to the ileo-colic sphincter is described by Elliott (1904). The splanchnic nerve, on excitation, causes its muscular cells to FIG. 97. EFFECT ON THE INTESTINE OF STIMULATION OF THE VAGUS NERVE. — Ninth period of stimulation. Slight preliminary inhibition, followed by powerful contractions, beyond the limit of the recording instrument.

contract instead of inhibiting their tone, as it does in the neighbouring parts of the small and large intestines. Adrenaline has the same effect. The significance of this fact in regard to the origin of the alimentary canal will be found in Gaskell's book (1908, p. 449). A fact which indicates the dependence on the central nervous system of those co-ordinated movements of the intestines which are not included in the myenteric reflex is described l>y Gottfried Boehm (1912). Cannon had shown that the food, after passing into the colon, is kept there for a time and churned backwards and forwards in order to ensure absorption ot

water and any products of digestion still left. Boehm found that excitation of the vairus nerve increased the vigour of the backward movements. The food, as it passes along the alimentary canal, is subjected to the action of a series of fluids containing enzymes, whose action will be described in the following section of this chapter. The modes in which the secretion of these juices is set going have been worked out almost entirely by Pavlov and his co-workers and will be found described in his book (1901). When references are given to this in the following pages, it is

to be understood that they apply to the English edition. A portrait of Pavlov will be found in Fig. 98. It will be noticed that that method of investigation which consists in the establishment of openings, or fistulse, in various parts of the alimentary canal plays a large part in work on the digestive processes. It is interesting to note that, so far as we know, Rene de Graaf (1677) was the first to make use of this method. In Fig. 99 his portrait is reproduced, There are several points of interest in the

title page to his book (Fig. 100). These will be found in the description ; what concerns us here is the dog in the foreground with salivary and pancreatic fistulae. For the various operative procedures required, the articles by Pavlov (1902) and by London (1910) may be consulted. Saliva. — This is the first fluid met with and it is produced even before the food enters the mouth. This " psychical secretion " is caused by reflexes through sight, smell, and so on ; the mouth "waters." The taste of the food in the mouth causes renewed secretion.

The Gastric Juice. — When the food enters the stomach, it finds that gust ric juice has already been secreted. This first secretion is psychical and depend^ greatly on the appetite with which the eating of food is approached. It is produced before food actually enters the mouth and, in fact, the mere presence of food in the mouth, without appetite, does not excite secretion. When, therefore, Macbeth wishes for his guests that "good digestion" may "wait on appetite," he is merely expressing a physiological fact.

If solid food is introduced directly into the stomach through an opening, a gastric fistula, unknown to the dog under experiment, no secretion is produced for an hour or more. Mechanical stimulation of the mucous membrane of the stomach is also ineffective. The efferent nerve through which the glands of the stomach are excited is the vagus. Certain chemical substances introduced into the stomach produce a secretion. According to Edkins, as mentioned already, a hormone, analogous to the pancreatic secretin, is produced from the mucous membrane of the pyloric portion and carried in the blood to excite the glands of the fundus. The experiments of Pavlov in connection with the chemical mechanism were performed mainly on dogs provided with a miniature stomach, separated from the main one by an ingenious operation, which is a greatly improved form of a similar one done by Heidenhain (see p. 13 of Pavlov's book). This miniature stomach was found to serve as a sample or indicator of all that proceeded in the main stomach.

It was found that meat juice or Liebig's extract caused secretion ; but no result was obtained from raw egg white, nor from starch nor fat. That the mechanism is a chemical one and not nervous is shown by the fact that Liebig's extract and similar substances are effective after the vagus nerves have been divided. The Pancreas. — The mode of excitation of the pancreas was described in the previous chapter. We see that the acid gastric contents, when they arrive in the duodenum, give rise to the production of secretin, which excites the pancreas. Whether the vagus takes any part in the normal process we have seen to be doubtful. If it does so, there is a possibility of "psychical" secretion from appetite, in addition to the effect of escape of the acid " psychical " gastric juice passing into the duodenum.

The Bile is another important secretion poured into the intestine. Its function will be discussed presently. We have seen that the same acid extract of duodenum which excites the pancreas also causes the secretion of bile, so that the acid contents of the stomach when they arrive in the duodenum cause also a secretion of bile. We have no evidence of a nervous control over the liver, with the exception of vaso constrictor nerves to the branches of the portal vein.

Snccus Enlericus, as already mentioned, appears to be excited, in any particular part of the intestine, by the presence of pancreatic juice in the parts preceding this one. We may now proceed to describe the changes which the food undergoes in the several parts of the alimentary canal. Since most food is taken in the form of more or less solid masses, a means of disintegrating it is clearly of advantage for the ready access of enzymes Most animals possess some means of doing this. Masticating apparatus, such as teeth

and strong jaws, are common. In those birds which eat hard grains there is a powerful muscular organ, the gizzard, whose cavity contains small stones swallowed by the bird and acting as mill-stones grinding the food before it is passed on to the stomach for digestion. In animals which chew the cud, Ruminants, the grass, etc., after it has been roughly chewed in its first gathering, passes into a large receptacle, where it undergoes a softening process by the action of bacteria. It is then brought back into the mouth again, bit by bit, and thoroughly masticated before being again swallowed and passed into the digestive stomach.

In some animals, as the crayfish, there is a masticating apparatus in the stomach, which is followed by a kind of filter, so that food is not allowed to pass into the intestine, into which the chief digestive gland opens, until it has been adequately subdivided. The main purpose served by the saliva appears also to be a mechanical one, since in many animals it contains no enzymes. It enables dry food to be readily masticated and swallowed. In animals taking food containing starch, we find that the saliva contains an amylase, sometimes called "ptyalin," which converts starch into maltose and, under favourable conditions, by further hydrolysis to glucose. We have already seen how carbohydrate food, by some chemical mechanism, causes an increase in the amylase content of the saliva in man (Lovatt Evans).

Having commenced with carbohydrate, we will follow its progress further, and afterwards that of proteins and fats. Although ptyalin is a powerful enzyme, it has too little time to do much work while the food remains in the mouth. It is inactive in so strongly acid a solution as the gastric juice, but it has been shown by Griitzner (1905) that the food in the stomach does not at once come into contact with the acid secretion, especially that food which is latest swallowed, which lies for some time in the middle and is protected by that first swallowed. So that, if the food be mixed with blue litmus, the centre of the mass in the stomach remains blue for some time and amyloclastic action can proceed. In any case, starch that escapes the action of ptyalin meets with the pancreatic juice in the intestine, and the amylase contained therein effects complete hydrolysis.

As regards other carbohydrates, cane-sugar, maltose, and lactose are hydrolysed by appropriate enzymes formed by the glandular epithelium of the small intestine. The manner of dealing with cellulose is of some interest. An enzyme which acts on cellulose is found in seeds — barley, for example — and has also been observed in the alimentary canal of the mealworm and in the secretion of the " liver " of the snail (Biedermann, 1911, p. 980), which forms hexoses and pentoses from various celluloses. It attacks also mannanes, galactanes, etc., the so-called " reserve " or storage celluloses. But in the higher animals the assistance of bacteria, chiefly in the large intestine, is required. In the ruminants, bacterial action also takes place in the paunch, before the second chewing process. The large caecum present in those animals which take cellulose in quantities, such as the rabbit, horse, or sheep, will be remembered and the mechanism of the digestion of cellulose must be effective, since it is said that sheep will get fat on blotting paper. Now the difficulty is that bacteria carry the process of destruction too far, producing hydrogen, methane, carbon dioxide, and lower fatty acids. Pringsheim (1912), however, lias succeeded in showing that a bi-hexose, together with the product of its further hydrolysis, glucose, is formed as an intermediate product. These sugars were obtained by stopping the fermentation at its height by the addition of toluene. It is uncertain whether the antiseptic acts by destroying the particular organisms responsible for the production of hydrogen, methane, etc., or whether it sets free the cellulose-hydrolysing enzyme from an intracellular condition. It may possibly merely put a sudden stop to all further change, so that a certain amount of intermediate products are, as it were, caught on the way. In any case, the " cello-biose " and glucose were isolated from cultures with filter paper of de-nitrifying, methane-producing, or better, thermophile bacteria. The sugars had been produced from the paper.

It is interesting that cello-biose is also hydrolysed by emulsin. There seems to be no doubt that the glucose is, in great part, absorbed from the alimentary canal before the bacteria are able to complete its destruction. Absorption of Sugars. — It is a remarkable fact that no absorption of digestive products takes place in the stomach. The chief absorption is done in the small intestine. Digestion and Absorption of Proteins. — The saliva contains no enzyme which acts on proteins. But in the stomach they are acted upon by a powerful hydrolysing enzyme, pepsin, which acts only in acid solution. Hydrochloric acid is secreted by glands in the wall of the stomach, and is of very wide distribution, being found even in the selachian fishes. It appears that, under usual conditions, pepsin does not carry the hydrolysis beyond the stage of the higher polypeptides, known as peptones. These are not absorbed, but passed on to the duodenum to be acted on further. The acid of the stomach has also a function as an antiseptic ; not a very powerful one, however, since we know that certain bacteria, for example the Bulgarian lactic acid bacillus, can be introduced into the intestine by way of the mouth. Acid, in any case, is a very unfavourable medium for the growth of bacteria, and hydrochloric acid in the concentration of that in the sto*mach kills a large number. We saw that the first stage in the fate of bacteria in the food vacuoles of amoeba, or phagocytes, takes place in an acid reaction ; but no digestive process commences until the reaction changes to an alkaline one. The acid reaction is associated with the killing of the organisms taken as food.

As the acid contents of the stomach are allowed to pass in small portions at a time into the duodenum, pancreatic juice is poured out by the mechanism already described (page 344), and further hydrolysis of the peptones formed in the stomach, together with that of any unattacked protein, is brought about by trypsin, in an alkaline solution. This alkalinity is not so great as was thought at one time, and as that of the pancreatic juice as it leaves the duct might lead one to suppose. There is considerable neutralisation by the acid of the stomach contents when they mix with the pancreatic juice. In fact, according to Michaelis and Davidsohn (1911), the optimal hydrogen ion concentration for trypsin is lO^8 normal, which is only just faintly alkaline to phenolphthalein.

We have already seen that the pancreatic juice does not contain active trypsin, but only its zyraogen, and that it is necessary for it to be acted upon by another enzyme, enterokinase, produced by the cells of the small intestine, for conversion into active enzyme. As shown by Mellanby and Woolley (1912), this process of activation has a remarkable time course. It starts slowly and becomes more and more rapid as it proceeds. Whether it has the typical S-shape of the curve of autocatalysis is difficult to make out, but it continues to accelerate in rate until the reaction is practically complete. No satisfactory explanation has yet been given of this phenomenon. According to Vernon (1913), it is due to the production of an unstable substance, which itself acts as an activator, but is rapidly destroyed. Ordinary trypsin, in fact, does not activate trypsinogen.

It is evident that some kind of autocatalysis takes place in the activation of trypsin. It may be that some product is formed by the action of enterokinase, which product has the property of increasing the activity of the enterokinase. Vernon (.Biochemical Journal, 8, p. 528) holds that the trypsin, as it is set free, acts upon some precursor with the formation of another enzyme, "deuterase," which itself activates trypsinogen, independently of enterokinase.

Bernard (1856, p. 513) refers to the fact that pancreatic juice is much more active when mixed with the contents of the duodenum. In fact, it does not appear that he had found it, as secreted, to act on proteins to any perceptible extent. His attention was thus dimud chiefly to its action on fats and on starch. The facts serve to show Bernard's experimental skill, since it is evident that he had obtained pure juice without contamination. Trypsin hydrolyses proteins to amino acids. There are, however, as seems probable, some of the simpler di- or tri peptides which are not attacked very rapidly by it. These are hydrolysed by the erepsin of the succus entericus, an enzyme which does not act on proteins themselves, or rather only on caseinogen and fibrin, and on these only slowly, but converts peptones and other polypeptides into their component amino-acids. It was discovered by Cohnheim (1906).

London (1906, etc.), using the Pavlov method of fistula? in various parts of the alimentary canal, has found that proteins are practically entirely converted into ammo-acids and absorbed as such in the small intestine. One of these, arginine, a conjugated di-amino-acid, as we have seen, is further hydrolysed by an enzyme, arginase, into urea and di-amino-valerianic acid. This enzyme was discovered by Kossel and Dakin (1904). Digestion of Fats. — A lipase -has been described by some as present in the stomach, but its function is negligible compared with that of the pancreatic juice. The action of this latter is assisted by the bile, which promotes fine emulsification, owing to its power of reducing surface tension, and as we have seen', it also has a direct effect on the activity of the enzyme. The bile also acts as a solvent for the free fatty acids, especially important in the case of the higher ones, such as stearic, etc. By this means, fats are hydrolysed into their constituent fatty acids 'and glycerol.