It is well established that acid chyme in the duodenum is the normal stimulus to the secretion of pancreatic juice.[31] Interaction of the acid with the duodenal mucosa liberates into the blood stream a substance which, circulating through the pancreas, excites the latter to activity. This exciting substance has been termed “secretin.” It can be prepared artificially by macerating duodeno­jejunal mucosa in 0.4 per cent. hydrochloric acid, neutralizing the boiling mixture, and filtering. A few cubic centimeters of the filtrate injected into a vein produce invariably a powerful secretion of pancreatic juice.[32] That a “chemical messenger” is at the basis of the duodenal acid reflex has been proved by even more crucial experiments—transfusion (Wertheimer,[33] Enriquez and Hallion[34]), cross circulation (Fleig,[35] Matuso[36]), and perfusion of the isolated pancreas (Huston[37]).

PROPERTIES OF SECRETIN

Prosecretin.—Secretin is soluble in water, yet a watery extract of intestinal scrapings is without action,[32] even after being submitted to acid treatment.[38] Starling therefore holds that secretin exists in the intestinal mucosa in an inactive form, as “prosecretin.” The content of the intestine in prosecretin decreases from the duodenum down, so that one is unable to demonstrate any prosecretin in the last 21⁄2 feet of the ileum. Prosecretin is insoluble in water, acetone, absolute alcohol or ether. Secretin, on the other hand, is readily soluble in water, normal salt solution and diluted alcohol (70 per cent.), but likewise insoluble in absolute alcohol and ether.

Preparation.—All of the more dissociated acids liberate secretin from intestinal mucosa on boiling. Their action is dependent on the degree of dissociation,[39] carbonic and boric acids being inactive.[40] Secretin can also be prepared with strong soaps (from 10 to 30 per cent. sodium oleate), alcohol (70 per cent.,[41] 0.6 per cent. sodium chlorid[36]). The acid and soap in the duodenum produce secretion; there is no necessary correspondence between the action of a substance in the intestine and that obtained by injection after boiling mucosa with it. The sodium chlorid, bile, maltose and glucose produce some secretion by the latter method yet none by the former.[36] On the other hand, ether, chloral and oil of mustard excite secretion when in the intestine, but no secretin can be prepared from boiled mucosa by their action. The irritation of the lining cell has produced the necessary hydrolysis.[38] In well-controlled experiments, Wertheimer and LePage[42] found that after the introduction of acid, secretion is secreted into the lumen of the intestine. Matuso[36] confirmed their results, and found this a satisfactory method for the preparation of secretin. It is said that secretin can be obtained by merely boiling the mucosa with water, but the results are inconstant.[43]

Action.—Secretin is an excitant not only of the pancreatic juice but also of the liver and the intestinal mucosa. The flow of bile is markedly accelerated (Henri and Portier,[44] Enriquez and Hallion[45]), likewise that of succus entericus (Delezenne and Frouin,[46] Bottazzi and Gabrielli[47]), and intestinal peristalsis is stimulated (Enriquez and Hallion,[48] Falloise[49]). Injections of secretin produce a marked vasodilatation, but the secretory effect is independent of the blood pressure changes. The pancreas is not readily fatigued by secretin. Bayliss and Starling[50] have obtained undiminished flow after eight hours of continuous injection. Our experience confirms this result. Also, equal doses of secretin give corresponding results at various intervals. Moreover, anesthesia does not affect the flow. Secretin is unrecoverable from the glands even after two hours of continuous injection.[51] The juice obtained by secretin has been subject to many studies.[52] It is of high alkalinity (about seventh normal), contains all the pancreatic ferments, and corresponds in all respects to the juice obtained in digestion from permanent pancreatic fistulas.[53]

Specificity.—In a maceration of the duodeno­jejunal mucosa, such as we have in secretin, the known substances are proteoses and peptones, acid amins, bile salts, beta-imidazol­ethylamin, cholin, gelatin and inorganic salts. These substances, individually and severally, together with their derivatives, are devoid of secretory action. Chemically, secretin, is then a specific entity. But like epinephrin, in its distribution, it is nonspecific. Active preparations have been made from an extraordinary variety of animals among the different classes of vertebrates (Camus,[54] Bayliss and Starling,[55] Chapman[56]). It is likewise found in the new-born and in the fetus.[57] Its action, however, like its chemical composition, is markedly specific. It stimulates the flow of pancreatic juice, bile and succus entericus. Its effect on the gastric glands is negative, and on the saliva likewise.[58] On the other hand, no other extracts produce pancreatic secretion. Dr. Koch, who, in collaboration with Dr. Keeton and Dr. Luckhardt, has done the most recent work on gastrin[59] (a substance that most nearly resembles secretin) and has isolated an extremely active preparation, finds that gastrin injection has likewise no effect on the pancreas. Camus and Gley,[60] with crude preparations, had previously obtained a similar result.

Lability.—Neutral secretin is but feebly attacked by a temperature of 100 C. If heated in an autoclave (so as to prevent oxidation), this temperature can be continued for thirty minutes without any change in its activity. Increasing the temperature increases the speed of destruction, so that at 140 C. the destructive action is marked.[61] Autoclaving at 15 pounds for fifteen minutes, as an ordinary sterilization of culture mediums, produces, we found, a distinct though not serious decrease in activity. Secretin acidified to fifth-normal with hydrochloric acid loses 60 per cent. of its activity on fifteen minutes boiling. Secretin, alkalinized to fifth-normal with sodium hydroxid loses 95 per cent. of its activity in five minutes’ boiling; decreases to a trace in thirty minutes, and disappears entirely in sixty minutes. At room temperature, with fifth-normal alkalinity, 80 per cent. of secretin is destroyed in eight hours.[61] The destruction probably means a secondary cleavage of the secretin molecule itself.

Secretin is oxidized readily. If left standing uncovered for a summer’s day, the preparation will be inactive.[51] Even if kept in the ice-chest (no other precaution being taken), its activity is lost in a very few days. Sunlight undoubtedly hastens the oxidative process. If care is taken as to sterility, however, and the secretin is kept in the ice-chest, well stoppered and in a dark flask, it will retain its activity for several weeks.

Dixon and Hamill[51] claimed that secretin disappears quantitatively on passage through a Berkefeld filter at 5 mm. pressure. Lalou,[62] using higher pressure, was unable to confirm the finding, but obtained a marked decrease in activity. Our results are in accord with those of Lalou.

Analogy to Epinephrin.—The analogy of secretin to epinephrin does not generally receive enough emphasis. Both substances are nonspecific in distribution, but specific chemically, and especially physiologically, epinephrin acting on the myoneural junctions, secretin on intestinal digestion. They are both relatively simple substances of low molecular weight, and subject to rapid oxidation whereby their properties disappear. The action in both cases is very transient. They are the two examples of what Starling calls the “acute hormones,” in which it is essential that reaction take place immediately, and shall disappear as soon as the exciting cause is removed.[63]