Principles of General Physiology

Strychnine and chloroform show their usual actions of converting inhibition to excitation, or excitation to inhibition, respectively, on the vasomotor reflexes. Owing to the complex nature of these reflexes effects are sometimes produced of a nature difficult at first to analyse. The effect of products of metabolism of active organs is to cause dilatation of the blood vessels, thus ensuring an automatic regulation of blood supply. But the facts do not account for the whole of the vaso dilator phenomena met with, which require the existence of vaso-dilator or inhibitory nerves.

The reflex secretion of adrenaline is not necessary as an accompaniment of pressor reflexes, so that we require also the existence of a vaso-constrictor centre. There is some evidence that the muscular wall of the arterioles responds to stretching by a contraction, but the question is not yet definitely decided. The coagulation of the blood is an interaction between certain colloidal systems under the influence of electrolytes, chiefly calcium salts. The intervention of surface action is shown by the accelerating effect of rough surfaces and by the action of lipoids.

THAT there are a number of poisonous substances which act on living organismin very minute doses has been known for centuries, but the fact that there are also many chemical compounds which are indispensable to the normal activities of organisms, although present in infinitesimal amount, has been recognised, in its full import, only in recent years. We have seen instances in the " accessory factors" of diet (pages 254-261), in the chemical mechanism of secretion, and of vascular dilatation and constriction, as wett as in enzymes and catalysts in general. In most of these cases the active substance is present in such extraordinarily small amount that, at present, it seems almost impossible to discover its nature. In some few cases the chemical nature is known.

The Minuteness of the Quantity necessary is made clear by the work of Bertrand on the action of zinc and manganese (pages 221-222 above), and that the phenomenon is not peculiar to living protoplasm is shown by the experiments of Elissafov on the action of thorium on the sign of the electric charge on surfaces. Thus the presence of 0*2 mg. of thorium nitrate in a litre of water lowered the rate of movement through a quartz capillary, under the action of electric forces, by 50 per cent. Other cases will appear presently. The nature itself of catalytic action, indeed, implies that only a very minute amount of a catalyst is necessary in order that an effect may be produced.

When we came across the mode by which the pancreas is excited to activity, it became obvious, to Starling and myself, that the chemical agent concerned is a member of a class of substances of which others were previously known. The peculiarity of these substances is that they are produced in one organ, and carried by the blood current to another organ, on which their effect is manifested. Since some confusion has been introduced into the nomenclature of the subject, a few words are necessary as to the history of the name.

The group of substances referred to, which includes adrenaline and the various internal secretions, is characterised by the property of serving as chemical messengers, by which the activity of certain organs is co-ordinated with that of others. They enable a chemical correlation of the functions of the organism to be brought about through the blood, side by side with that which is the function of the nervous system (see the Croonian Lecture by Bayliss and Starling, 1904). This being so, it seemed desirable and convenient to possess a name to distinguish the group. That of " internal secretions," already in use, did not sufficiently emphasise their nature as messengers. After the discovery of secretin, this name for the group was for» long time a subject of discussion in the laboratory, but no satisfactory name was suggested. Finally, Mr W. B. Hardy proposed the name "hormone," derived from opfidu ("I arouse to activity"), and, although the property of messenger was not suggested by it, it was adopted. It has, in fact, been generally understood as having the meaning intended, and not to be applied to any kind of substance which excites activity. Indeed, a name of such very wide application would be of comparatively little value. I may give three quotations to show that this property of messenger is usually understood in the use of the word "hormone." Gley (1911, p. 19, footnote) points out that the "excitants fonctionnels (hormones de Bayliss et Starling) " are of two kinds. We shall presently return to this distinction, but the point is that Gley insists on the correlation established between different organs " par 1'intermediaire de substances secretees par des glandes speciales et deversees dans le sang qui les transport* la ou elles peuvent agir" (p. 21). Again, Hustin (1912, p.

319) says — " Bayliss et Starling donnerent le nom cThormonffi (6pfuiu, j'excite) £ ces substances qui constituaint, comme la 9ecrttine, des intermediates chimiques entre des organes voisins ou situes & distance." Babkin (1914, p. 5)>-ays — " Die Hormone bilden die Vermittler zwischen den verschiedenen Teilen des Korpers (Bayliss und Starling)." When, therefore, the name is extended to apply to such substances as chloroform or toluene, which set into activity enzymic changes in cells because they are able to penetrate the cell membrane and enable interaction to take place between constituents within the cell (H. E. and E. F. Armstrong, 1910, 1911), it appears to me that the original meaning of the word is deprived of significance and applied to cases of a different kind, for which there does not seem to exist the necessity for a special name.

It may be added that this conception of co-ordination by chemical messengers is to be found in a note by Brown-Sequard and d' Arson val (1891), who say — " Nous admettons que chaque tissu et plus generalement chaque cellule de 1'organisme secrete pour son propre compte des produits ou des ferments speciaux qut sont verses dans le sang et qui viennent influencer par 1'intermediaire de ce liquide toutes les autres cellules rendues ainsi solidaires les unes des autres, par un mecanisme autre que le systeme nerveux."

When we look around the numerous examples of such influence of minute traces of substances formed by one organ and acting on other organs, we note that there are not many so definite as that of secretin, where the food entering the duodenum causes the production of a special substance which enters the blood and excites the pancreas to pour into the duodenum a digestive juice, and, so far as we know, does not act on any other organ except the liver, whose secretion is an adjuvant to that of the pancreas.

Gley (1911, p. 19) rightly calls attention to the fact that some of the substances which act like hormones in modifying the activity of distant organs, such as carbon dioxide on the respiratory centre, are really products of the ordinary metabolism of cells, and are not, like secretin, produced for a specific purpose. The delicate sensibility of a particular nerve centre to carbon dioxide must be supposed to be an adaptation developed in the course of evolution. Gley suggests calling these latter substances " parahormones." He also points out the convenience of a name for that class of hormones which influence growth, and proposes that of harmosones (from ap/j.6£<», I regulate or direct).

When distinction is required between the different classes of hormones, these names appear satisfactory. On the other hand, the distinction made by Schafer (1913) between substances which excite (hormones) and those which depress (chalones) activity, seems unnecessary, as also the name "autacoid" to include both. If we interpret, as we are justified in doing, "excitation to activity" as being equivalent to "bringing into play an influence on cell processes," this influence may be of such a nature as to inhibit. Moreover, such a typical hormone as adrenaline excites blood vessels to contraction, but inhibits the muscular coat of the intestine, so that it is both hormone and chalone, according to the particular way in which the sympathetic end organ, on which it acts, terminates in the cell.

The name " internal secretions " has been given to many of the substances with which we are here concerned ; this was done before the discovery of secretin. The fact that many organs deliver the products of their activity into the blood current was well known to Claude Bernard (1859, ii. pp. 411, 412), and the name "internal secretion" is due to him. The products of organs such as the suprarenals, the thyroid, and so on, are those to which the name is given.

Before we pass on to consider some facts in relation to various individual hormones, the considerations of Hopkins, to which attention was directed above (page 20), should be remembered. An intermediate product in a chain of reactions, although its concentration in the system at any given moment may be infinitesimal, is probably of great importance as a necessary stage. The amount present may be small because the rate of the reaction producing it may be slow, compared with that of the reaction by which it is changed into a further product.

Secretin. — As already pointed out, the most typical of all the chemical messengers is that which causes secretion of pancreatic juice when acid enters the duodenum. This mechanism was described in a previous chapter (pages 344 and 346). The view of Popielski that the effect on the pancreas is merely due to the presence of a vaso-dilator substance is easily disproved in many ways. Bayliss and Starling (1902, 1, pp. 336, 337) showed that the fall of blood pressure could be prevented by extraction of the raucous membrane with absolute alcohol before boiling with acid, and that acid extracts of desquamated epithelial cells of the intestine had no action in depressing the blood pressure, although very active on the pancreatic secretion. Recently Launoy and Oeschlin (1913) have confirmed this conclusion in a completely convincing manner. Although the substance acting on the pancreas is soluble in 90 per cent, alcohol, it is insoluble in absolute alcohol. Thus, if concentrated aqueous solutions of secretin, prepared in the usual way by the action of hydrochloric acid on the duodenal mucous membrane, are poured into excess of absolute alcohol, a precipitate is obtained. This process, several times repeated, results in the production of a white powder, easily soluble in water, insoluble in absolute alcohol. As Fig. 251 shows, it ha* a powerful secretory action but no depressor action on the blood pressure. On the other hand, the alcoholic mother-liquors, concentrated, give a powder of yellowish colour, also soluble in water, which has a powerful effect on the blood pressure, together with a very small one on the secretion, no doubt due to small amounts of secretin left unprecipitated. From the work of Dale and Laidlaw (1910), it seems more than probable that the fall of blood pressure is due to /i-iminazolylethylamine.

As yet we have no definite knowledge of the chemical nature of secretin. It is evidently an intensely powerful substance, but does not appear to have a very complex structure, since it is diffusible through parchment paper. It is, naturally, incapable of acting as an antigen, since the production of an anti-body in the blood would be antagonistic to its function. The statement also applies to other hormones. It was suggested by Bayliss and Starling that secretin is produced by the action of acid on a precursor in the cells of the mucous membrane. To this supposed precursor the name " prosecretin " was given. A certain amount of discussion has since taken place as to whether secretin itself is not present in the cells. The work of Stepp (1912) shows that it may occasionally be present in small quantities, so that mere extraction with boiling water is sometimes sufficient to obtain solutions of active secretin, as was indeed found by Bayliss and Starling (1902, 1, p. 340). In most cases no such effect was obtained. In certain of these cases it was found that the slightly alkaline opalescent solution, obtained by boiling and filtering, contained a substance from which, by boiling with acid, an active secretin was obtained. These results indicate that the cells usually contain a precursor, but it is not surprising to find that it should sometimes happen that the secretin produced by action of acid, etc., on these cells has not completely passed away into the blood stream. Stepp also comes to the conclusion that, however prepared, secretin is one and the same substance. He gives a method by which a permanent dry preparation can be obtained, which is similar to that of Launoy and Oeschlin, but giving a better yield by the use of ether to precipitate.

The method of preparation of very active solutions, worked out by Dale and Laidlaw (1912, 1), depends on the fact, that mercuric chloride precipitates secretin as a mercury compound, soluble in dilute acids, insoluble in neutral or weakly alkaline reaction ; it may, however, merely be held in adsorption by a substance having these properties. In this method, a large amount of impurity is stopped at the outset. It was easy to obtain a preparation of which 1 c.c. produced 8-5 c.c. of juice.

We may next consider briefly some results obtained by Lalou (1912, 1). Bayliss and Starling noted the fact that solutions of secretin introduced into the lumen of the gut failed to excite the pancreas. Hence the agents causing the production of secretin, when they are introduced into this cavity, must act directly on the cells and, at the same time, enable the secretin to pass into the blood vessels. Lalou calls attention to the fact that various agents, such as saccharose, urea, etc., produce secretin by action on the mucous membrane in vitro, but do not excite pancreatic secretion in the living animal. It has not been shown as yet, however, that such agents, which destroy the cells in vitro, really produce secretin in them ia the living state, so that it seems to me that the

FIG. 251. ACTION OF SECRETIN ON THE FLOW OF PANCREATIC JUICE. In both tracings, the top line registers the drops of juice falling from a canula in the pancreatic duct. The curve below it shows the arterial pressure, with scale in centimetres at the side. In the upper tracing, time is shown in minutes below the drop recorder. The upper tracing shows the effect of secretin from which the depressor substance had been removed by extraction with alcohol in the manner described in the text (page 708). There is no fall in blood

pressure but a vigorous flow of juice. The lower tracing shows the effect of the depressor substance extracted from the raw secretin. It still contained a certain amount of the active secretin. There is a large and prolonged fall of blood p-essure, probably due to /3-iminazolylethylamine, but only a small secretory effect. distinction drawn between excitants such as hydrochloric acid, which enable secretin to be absorbed, and those above named, which produce it, but without enabling it to be absorbed, is not a valid one. In a further paper (1912, 2) Lalou investigates the behaviour of secretin towards chemical agents, with a view to elucidating its nature. The most interesting fact is that it is rapidly destroyed by pancreatic and gastric juices, by erepsin in neutral solution, and by pa pain. In connection with this fact, a discovery by Delezenne and Pozerski (1912) is of interest. They showed that extracts of various tissues containing erepsin, especially the mucous membrane of the intestine, have a powerfully destructive action on secretin. This fact has to be kept in mind when extracting the mucous membrane with cold water.

Gley (1-912) gives a classification of the various chemical excitants of pancreatic secretion. The complete proof that secretin is present in the blood of an animal after the introduction of acid into the duodenum was given simultaneously by Fleig (1903) and by Enriquez and Hallion (1903), who found that the blood of a dog, in which pancreatic secretion had been induced by the introduction of acid into the duodenum, was capable of producing activity of the pancreas in a second dog.

Gastric Secretion. — The observations of Pavlov showed that the introduction of meat into the stomach caused secretion in an isolated small stomach, even when nervous influences were excluded. Edkins (1907) showed that extracts of the pyloric mucous membrane, made in various ways, but especially by the action of dextrine, caused increased formation of an acid gastric juice. Maydell (1913) confirmed the fact, in so far as that subcutaneous injection of extracts of pyloric mucous membrane brought about increased secretion in a dog with a chronic gastric fistula. The most active preparation was found to be made by extracting pyloric mucous membrane with 0'4 per cent, hydrochloric acid at ordinary temperature. Immediately before injection this was neutralised. Extracts of other parts of the stomach or of the duodenum were ineffective. Comparing the properties of the juice obtained from the same animals by " sham feeding," that is, the juice obtained by natural stimulation of the vagus, the acidity was found to be about the same ; the digestive power was, however, considerably less in secretion obtained by chemical agency. Maydell was able to obtain a dry active preparation by the application of Stepp's method, described above for the pancreatic secretin.

Adrenaline. — Brief reference has been made already to the action of the product of activity of the suprarenal glands. The first investigation of the properties of this substance was made by Oliver and Schiifer (1895), in so far as concerns extracts of the organs. They showed also that' the pressor substance is contained in the medulla only. The active principle, "adrenaline," was isolated by Takamine (1901) and found to be and may be regarded as a methyl-amino derivative of pyrocatechol. Since this contains an asymmetrical carbon atom, there are two optical isomers. In the suprarenal glands the /-form only occurs. The racemic mixture has been prepared synthetically by Stolz (1907), and found to be rather more than half as active as the natural form ; hence the d-isomer is much less active than the /-isomer. An instructive case of similar difference of activity in optical isomers will be referred to in the case of hyoscine on a later page.

The similarity of the structure of adrenaline to that of tyrosine or homogentisic acid (see page 432 above) will be noticed, and it has been stated that the suprarenal gland mixed with tyrosine in vitro is able to produce adrenaline from the amino acid ; but further investigation failed to confirm the statement. The occurrence of adrenaline in the secretion of the " parotoid " glands of a toad, described by Abel (1913), indicates that it may be a more or less accidental product of metabolism in itstirst appearance.

It is an intensely active substance. Pysemsky and Kravkov (1912), in perfusing the ear of the rabbit with Ringer's solution, to which adrenaline was added, found that one part in two hundred and fifty millions of the saline solution could be detected. The cells which secrete adrenaline, that is, those of the medulla of the glands, stain a brownish-yellow colour with potassium bichromate ; hence the name given to them of " Chroniaffine " tissue. Similar cells are found throughout the vertebrate kingdom in various situations. In the lamprey the system is arranged segmentally. The reaction is also given by certain nerve cells in invertebrates, and J. F. Gaskell (1914) points out that the presence of such cells is correlated with the development of a contractile vascular system. In the leech, each segmental ganglion contains six chromaffine nerve cells, and the contractile vascular system consists of a series of segmental units, each under the control of a segmental ganglion. The chromaffine cells contain a substance similar to adrenaline, and the contractile vessels react to adrenaline as those of the vertebrate do. There appears then to be some close connection between these chromaffine nerve cells and those of the medulla of the suprarenal bodies ; moreover, the relation between the action of adrenaline and the sympathetic system, already spoken of, shows a further connection. J. F. Gaskell suggests that the chromaffine nerve cells of the invertebrate are the common ancestors of the adrenaline-secreting chromaffine system and the sympathetic nervous system of the vertebrate. Thus we find the contractile vascular system regulated both by the sympathetic nerves and by secretion of adrenaline.

Further evidence is found in the mode of development of the medulla of the suprarenals. As Balfour showed (1878, pp. 242-245), this has the same origin as the sympathetic system, and Kohn (1902) showed that the development of these cells of the medulla is from a series of groups of cells in connection with the sympathetic along the body axis. Rudiments remain for some years in scattered situations, as along the aorta and to form the carotid gland, but the main mass becomes the suprarenal ganglion, or medulla of the suprarenal body. The scattered remains are called paraganglia.

We have seen that one of the characteristics of the sympathetic outflow is the connection of each fibre with a cell before passing on to its destination. Now Elliott (1913, 2) has shown that the supply to the adult suprarenal gland has no cell station previous to the cells of the medulla themselves, a further fact in evidence of the similarity of these cells to those of the sympathetic ganglia. Elliott (1913, 1) points out that there are two types of cells to which the sympathetic fibres from the spinal cord pass : —

(1) The sympathetic ganglion cell, which is distally united to the plain muscle cell by its axone process, and so provides a path for the nervous impulse. (2) The medullary or paraganglion cell, which is not in connection with the muscle, but is equally innervated from the spinal cord, and secretes a chemical substance into the blood, which can produce an identical stimulation of the muscle through its myo-neural junction. These may have been originally identical, and the liberation of adrenaline an essential part of the nerve impulse. But, at the present time, the paraganglion cell secretes adrenaline, which maintains the smooth muscle in a state of excitability, ready to react to the nerve impulses from the sympathetic fibres. Elliott's general scheme is reproduced in Fig. 252.

Fascinating as this scheme is, there are some minor points which are not completely cleared up. The sweat glands, although innervated by the sympathetic, are not excited by adrenaline. Further, we have seen that the presence of the suprarenal bodies is not necessary for the production of vascular constriction. It may well be, however, in this latter case, that the loss of excitability does not take place rapidly. Elliott (1912) has shown that the various states associated with stimulation of the splanchnic nerves cause discharge of adrenaline into the blood, causing rise of blood pressure, and the other results of sympathetic stimulation. Such states are fright, anaesthesia, stimulation of afferent nerves, and so on. Reference to the

.4, The non-ganglionated ordinary motor nerves to striped muscle, which are distributed si-^nifiitally only. On the left side these are omitted for sini)>licity, and only the autonoinic or gaiiglionated visceral nerves to plain muscle are indicated. Of these, B is the cranio-cervical outflow in the vagus, etc. ; C, the thoracico-lumbar or sympathetic proper ; O, the sacral outflow, or pelvic visceral nerve to the bladder and colon. All these subdivisions contain both excitatory and inhibitory nerves.

C, is the sympathetic ganglion cell ; C, the paraganglion cell, secreting adrenaline, the chief mass of these being concentrated to form the medulla of the adrenal gland, though a few, even in adult life, may be found elsewhere in relation to the various sympathetic ganglia. The black rectangle innervated by the nerves from the cells C, represents the mass of plain muscle which is also stimulated by adrenaline, that is, by the secretion of C.. Afferent sensory nerves and their posterior root ganglia are all omitted from the diagram. Their course from the viscera is not clearly known.