Principles of General Physiology

work of other observers will be found in the paper. Those of Cheboksarov (1910) may be especially mentioned. Suppose, then, that a drug is given which stimulates the splanchnic nerves. It is clear that the effects obtained will be combinations of those of the drug itself with those of the adrenaline sent into the blood. Dale and Laidlaw (1912, 2) have found that nicotine and pilocarpine produce effects of sympathetic stimulation on the cat's uterus in situ, but not when excised. Also the effect of nicotine in causing dilatation of the pupil, after the sympathetic supply had been cut off, was found to be absent if the suprarenal bodies were excluded from the circulation. The glycosuria produced by puncture of the floor of the fourth ventricle is probably also due to secretion of adrenaline.

Although, under experimental conditions, there seems to be no doubt that the blood of the suprarenal vein contains more adrenaline than that of the artery, some discussion has arisen as to whether the normal blood pressure is, under normal conditions, maintained to any extent foy a constant inflow of adrenaline. When the effect of the venous blood from the" suprarenal gland on the arteries of the frog is compared with that of known concentrations of pure adrenaline, and this again with the amount required to produce a permanent rise in the blood pressure of the mammal, it appears that the amount sent into the blood by the unstimulated suprarenals is too small to produce any perceptible result. Further, Trendelenburg (1914) was unable to find any difference between the average blood pressure in cats, unansesthetised and quiet, before and directly after removal of the suprarenals.

Adrenaline is, then, a hormone, used only for special purposes, and unlike some of those to be mentioned presently, which are in constant activity. The Cortex of the Suprarenals. — Elliott (1913, i. p. 316) points out the remarkable fact, although it does not appear to have any physiological significance, that so many ductless glands, the pituitary, suprarenals, thyroid, pancreas, testis, etc., are of double nature. This renders analysis difficult.

The cortex of the suprarenals has no particular relation to the sympathetic nerves. The presence of a considerable amount of a lipoid substance appears to be an indication of a healthy state of activity. It is supposed that the absence of the cortex is associated with the bronzing of the skin in Addison's disease. There is also evidence that overgrowth of the cortex in children is associated with sexual precocity and premature adolescence. Carbon Dioxide. — The distinction of this substance as a parahormone by Gley, and the development of special sensibility on the part of the respiratory centre to increase of hydrogen ion concentration in the blood, caused by its presence, have been already referred to. The work of Hasselbalch and Lundsgaard (1911), and of Hasselbalch (1912), may be added as containing the most accurate determinations of the hydrogen ion concentration of the blood in connection with stimulation of the respiratory centre.

It seems very doubtful whether carbon dioxide has any particular function as a hormone in any other respect. The "acapnia" of Mosso, as responsible or mountain sickness, has been shown by Haldane and his co-workers not to oe the correct explanation. Yandell Henderson has published a series of papers in the American Journal of Physiology, from 1908 onwards, advocating the importance of carbon dioxide as a necessary constituent of the blood, and explaining various phenomena as being due to its too small concentration. In so far as its removal reduces the optimal hydrogen-ion concentration for numerous processes, this removal has, of course, an injurious effect. ^ The evidence that other apparent effects cannot equally well be explained in other ways is not very strong.

The Reproductive Organs. — It has been known for centuries that removal of the sexual glands produces profound changes in the organism. But it is only comparatively recently that exact observations have been made on the phenomena. Perhaps the most striking results to commence our brief study with are those of Steinach (1910). If the testes are removed from frogs, the "clasp reflex" is abolished. Of course, the nerve centres concerned remain, and it is not

surprising that, after some time, indications of the reHex may return. The absence of it might depend, however, on the absence of afferent nervous impulses from the testes. Steinach, then, took a number of castrated frogs and tested for several consecutive days whether the reflex could be evoked. Having found that it could not, he injected, into the dorsal lymph sac, the substance of testes of frogs which had shown a marked reflex. After about twelve to twenty-four hours the reflex began to appear, reached a maximum in two days, and disappeared in three to four days, but could be brought back by renewed injections. No increased excitability in any other reflex could be detected, and it was noticed that the peripheral receptors, the swellings on the thumbs, were enlarged after injection of testicular material. The effect of the testis of the same species is the greatest, but it is not strictly specific, since that of Rana fusca will act on Jt. esculenta. The result was still more marked in cases, about 4 to 8 per cent, of the frogs caught, where the reflex was naturally absent. Steinach believes that the action is exercised, primarily, on the central nervous system, since injections of nervous matter from normal males caused the return of the reflex in castrated males ; while the central nervous system of castrated males had no such effect. The testes of males for two or three months after the breeding season were devoid of action, so that the hormone is formed periodically. It is supposed to act by depressing the activity of centres which inhibit that for the clasp reflex.

Further experiments were made on rats. Finding that feeding with testis material was ineffective, autoplastic transplantation in animals of three to six weeks old was performed. The testis was removed to various positions on the inner surface of the abdominal muscles in some animals, and removed altogether in other animals. In the -latter, no development of vesiculse seminales, prostate, nor penis took place. In those in which the transplanted testis grew, the development of the organs named was indistinguishable from that of normal males, and the animals behaved, sexually, just as these. The hormone concerned did not arise from the generative cells themselves, because they were not developed in the transplanted testis, whereas the interstitial substance was fully developed.

Interesting observations have been made by Marshall and Hammond (1914) on the effect of removal of the testes in Herdwick rams, where the operation is found to stop the growth of horns. It is shown in these experiments that the theory of Geoffrey Smith, according to which the effect of the testes is not due to a hormone, but to a process explained by Ehrlich's side-chain theory of the production of antitoxins, does not hold. Turning to the female, we find interstitial tissue in the ovary, as we saw in the testis, to which the development of sexual characters is apparently due. The changes taking place in the first stages of pregnancy have been shown by various observers to depend upon the development of the corpora lutea, which are formed in the place of the Graafian follicles after the ova have been extruded. The reader may be interested to examine Figs. 253 and 254, which are copied from Rene de Graaf's drawings of the follicles, which he discovered, and of the corpora lutea. The effect of tlie latter on the development of the mammary glands will be considered in the next section. In this place we may refer to the work of Ancel and Bouin (1910), who showed that the growth of the uterus is dependent upon that of the corpora lutea, since if these latter are formed in any way, the first stages of the uterine hypertrophy occur, although there may be no pregnancy. In this latter case the uterus returns to its original state. If the Graafian follicles are ruptured artificially, it is found that the uterine hypertrophy occurs, but only when a corpus luteum is formed. Further, if the corpora lutea are destroyed by the cautery when uterine hypertrophy has become obvious, the hypertrophy ceases to increase and rapidly disappears.

From the experiments of Marshall and Jolly (1908) and those of Nattrass (1910), it follows that a transplanted ovary, when it continues to live, is capable of maintaining the sexual characters of the individual. With regard to transplantations of the ovary, Guthrie (1908) believes that FIG. 253. REGNIEB DE GRAAF'S FIGURE OF THE OVARY OF THE cow BEFORE COITCS, CONTAINING RIPE OVA IN GRAAFIAN FOLLICLES. — His description of the figure is as follows : —

"Exhibet Testiculum give Ovarium Vaccinum apertum, prout illud ante coituni observari solet. G, Foramen coarctatum in Tubae extremitate existens. H, Tubae Fallopianse extremitas. L, Tubae Ligamentum in hominibus alls vespertilionum assimilatum. " FIG. 254. CHANGES OCCURRING AFTER COITUS. FORMATION OK CORPUS LDTEUM. " VaccsB et Ovis Ovarium exhibet, ut ea, quaa post coitum in illis eveniunt, conspieiantur. -I , Testiculus secundum longitudinem apertus : SB, Glandulosa substantia, quaa post Ovi i-xpulsionem in Testibus reperitur, per medium divisa ; CC, Cavitas, in qua Ovum contentum fuit, fere abolita; DD, Ova di versa) magnitudinis in Ovario contenta ; EE, Vasa sanpuinea ad Ova excurrentia ; F, Tubae Fallopianae membranosa expansio complicata ; G, Foramen in extremitate Tubarum existens ; II, Tubae Fallopianaa pars abscissa. Fig. II. Exhibet Testiculum necdum apertum. .1 , Testiculus ; /.', Glandulosa substantia extra Testiculum protuberams ; C, Foramen in ejus

medio existens ; D, Tubae Fallopianaa membranosw expansionis jwrtio. Fig. III. Exhibet Testiculum Ovillum cum t ransimrentibus Ovis necdum masculino semine irroratis. Fig. IV. Exhibet glandulosam globulorum substantiam ex Ovis Testiculo exemptam prout Ovum adhuc continebat. A, Glandulosa globuli substantia adaperta ; B, Locus ex quo Ovum exemptum est ; C, Ovum ex Fig. V. Exhibet Testiculum Ovis ex quo Ovum ab aliquot diebus expulsum fuit. .(. Testiculus per medio divisus ; I:. Glandulosa globulorum substantia cum cavitate sua propemodum abolita ; CC, Ova^diversae magnitudinis in Testium superflcie haerentia ; DD, Vasa sanguinea ad Ova excurrentia ; E, Ligamenti Testiculonim portio."

he has obtained evidence that the " foster-mother " has an influence on the offspring. He took hens of black and of white Leghorn varieties, which were Fio. 255. GROWTH OF MAMMARY GLAND OF RABBIT CAUSED BY FORMATION OF CORPUS LUTEUM. B, Two glands, five days after coitus not resulting in fertilisation. C, Two glands of virgin rabbit, four days eighteen hours after appearance of corpora lutea, provoked by artificial found to breed true, when mated with cocks of their own colour. The ovaries were then interchanged. Subsequently they were mated with cocks of the colour corresponding to the transplanted ovary, but opposite to their own colour.

The majority of the offspring were found to be spotted. For instance, when the ovary and the male were pure white, the foster-mother pure black, the chickens had black spots. Should this turn out to be correct, we see a possibility of the disputed " Sran#mi#*ton ofacqiiirtd characters" since the body of the mother affects the germ plasm. In respect to the question in general, the remarks of Shattock (1911, pp. 26-34) will be found of much interest. He shows that the callosities of the monkey are not to be attributed to transmission of

FKJ. 256. SECRETION OF MILK IN THE OAT, PRODUCED BY INJECTION OF PITUITARY EXTRACT Middle signal, injection of saline extract of ten pituitary glands of the fowl. a character acquired by friction. A callosity acquired in this way is not transmitted, but has to be regained after birth. The Mammary Gland. — The growth of this organ is closely connected with that of the uterus in pregnancy, so that it is not surprising to find that the growth is affected by a hormone produced in the corpus luteum. This has been shown by O'Donoghue (1911, 1 and 2, and 1913) and by Ancel and Bouin (1911). The artificial production of corpora lutea by puncture of the G mafia n follicles is followed by growth of the mammary gland, as shown in Fig. 255.

The second stage, associated with secretory activity in the later period of pregnancy, is independent; of the corpus luteum. It has been shown by Mackenzie (1911) that the gland is not under the influence of the nervous system, but that extracts of various organs, injected into the blood current of a cat in lactation, cause secretion of milk. The organs found active were the pituitary body, the corpus luteum, the pineal body, the involuting uterus, and the mammary gland itself. The pituitary body is by far the most active; the substance responsible is in the posterior lobe, and that of the bird is capable of exciting the mammary gland of the cat (see Fig. 256). The foetus and placenta produce hormones which inhibit the gland. Further analysis of the action of pituitary extract was made by Hammond (1913). The effect is said not to be due to pressing out of milk by contraction of muscle in the ducts, since, with other evidence, after increase of secretion there is no sudden drop, followed by return to the normal rate, as would be the case if the ducts had to be refilled. The daily yield of goats was found to be only slightly increased by injections, so that pituitary extract seems to act by setting free the constituents of the milk, rather than by causing increased formation. The theory is suggested that the precursor of milk-protein and lactose (perhaps a glyco-protein) is caused to take up water, become hydrolysed, and by the increased osmotic pressure cause the inflow of water to the cells and the washing out of the fat which has accumulated at the ends of the cells.

The Pituitary Body. — In addition to the effect on the mammary gland just described, and that on the kidney referred to on page 359 above, this organ has other effects, especially on growth. The gland consists of two parts. From the posterior, nervous part the hormones above mentioned are obtained, together with one which excites plain muscle in general fo contraction. The anterior part secretes an eosinophile material, which, according to Herring (1908), passes into the third ventricle, and thus into the cerebro-spinal fluid..

Disease of the gland shows it to have a powerful influence on growth and metabolism. Gushing (1912) regards the state of acromegaly or gigantism as due to excessive activity, and that of obesity, with eunuchoid changes, as due to failure of pituitary hormone. The results of experimental interference are somewhat in dispute as yet. The Thyroid Gland. — Here, again, analysis is difficult because of the double nature of the organ. Definite information is wanting as to the relative functions of the two parts.

Absence of thyroid prevents growth, and produces the remarkable state of myxoedema, associated with cretinism. Excess of the hormone causes Graves's disease, exophthalmic goitre. In both cases curious nervous phenomena are met with. Gaskell (1908, Chapter V.) brings strong evidence to show that the thyroid gland of Ammoccetes, and therefore of vertebrates generally, is derived ancestrally from the uterus of the original palseostracan. There is still a connection between the generative organs and the thyroid which is a matter of popular knowledge, and it seems not unlikely that remains of the internal secretion may have continued when its original function ceased.

The most interesting fact, chemically, with regard to the thyroid is the high content in iodine, which appears to be present in a complex organic iodine compound, united with a protein. That this is the active principle is shown by the fact that the effect of thyroid substance, which is active even when taken by the mouth, is in proportion to its iodine content. The Thymus. — We are even more in the dark as to the function of this organ. There is evidence that it has some function in normal growth. It is large in the young animal, and becomes less and less as growth ceases. Its removal from the young animal has been stated to cause retardation of growth. Hainan and Marshall (1914), however, in careful experiments, found that removal of the gland from young guinea-pigs had no effect on their growth, nor when the testes were removed simultaneously. Castration, according to other investigators, leads to hypertrophy of the thymus, but Hainan and Marshall could find no evidence of any compensatory mechanism between the testes and the thymus.

The Internal Secretion of the Pancreas. — Mering and Minkovski (1889) showed that complete removal of the pancreas invariably results in severe diabetes mellitus. The animals excrete large amounts of glucose, even if no carbohydrate food is given. They show great hunger and thirst, and, in spite of liberal food, they die of inanition in the course of two or three weeks, or less. To obtain this result extirpation must be complete ; one fifty-fifth of the organ suffices to prevent the symptoms. Since total extirpation is of primary importance for success, the excellent method of removal introduced by Hedon (1910) may be referred to.

The glycogen vanishes from the liver in pancreatic diabetes, and although the glucose content of the blood may be raised to 0-8 per cent., no glycogen is stored, although it has been stated that fructose may give rise to glycogen in the liver. The meaning of this great loss of glucose is still obscure. Investigations directed towards testing the power of the tissues to consume carbohydrate have not been able to show that the power is entirely wanting (see the paper by Patterson and Starling, 1913), although it seems to be diminished, especially in the later stages.

Although no attempts to prevent the diabetes by the injection of extracts of pancreas have been successful, the transfusion experiments of Hedon (1913) show that the glycosuria is due to the absence of a hormone secreted by the normal pancreas. An anastomosis was made between the vein of the pancreas of a normal dog and the jugular vein of a depancreatised and diabetic dog. The glycosuria was almost abolished, and there was a diminution in the glucose content of the blood. That the liver plays an important part in the process is shown by the following variation of the experiment. A part of the normal pancreas of another dog was intercalated, by vascular anastomosis, in the circulation of a diabetic dog. This had a similar effect to the previous form of experiment, but only when the venous blood of the pancreas, presumably containing the hormone, was allowed to pass through the liver, by anastomosis with the splenic vein of the diabetic dog. The serum of the venous blood of the pancreas is said to have no anti-diabetic power. The fact of the relatively small effect on the glucose content of the blood leads Hedon to the view that the hyperglycsemia and the glycosuria are more or less independent. The blood sugar may be scarcely diminished at all when its excretion by the kidneys ceases owing to the influx of normal blood. But, since the blood sugar did not increase, it is clear that either the excess production had been retarded, or the rate of consumption by the tissues increased ; otherwise it must accumulate when excretion stops. These experiments indicate, then, (1) that the liver plays an important part, and (2) that there is some influence exerted by the pancreatic hormone on the excretion of sugar by the kidneys.

This latter may be either decreased permeability, or, perhaps more probably, an effect on the reabsorption in the tubules of the glucose contained in the glomerular filtrate. A third possibility is suggested by Hedon, namely, that there might be some change in the state in which the sugar exists in the blood. In connection with these results, the experiments of De Meyer (1906-1910) are of interest. He finds that the liver, perfused with Ringer's solution, loses less glycogen if pancreatic extract is added. If the liver came from a depancreatised animal, it was found that its function of storing glycogen could be restored by the perfusion of fluids containing pancreatic extracts. Perfusion with blood, instead of with Ringer's solution, showed still more marked effects of addition of pancreatic extract. Perfusion of the kidney with Ringer's solution containing glucose, together with pancreatic extract, showed that considerably less sugar came out in the secretion than in the absence of pancreatic extract. De Meyer finds that the addition of such extract to solutions of glucose -does not diminish its rate of diffusion through a colloidal membrane, and interprets the effect as being due to a diminution of the permeability of the kidney for glucose. It might, of course, be exerted on the power of reabsorption. The experimenter is inclined to attribute the action, both in the case of the liver and the kidney, to the increase of hydrogen ion concentration in the blood in diabetes, which is counteracted by the internal secretion of the pancreas.

The experiments of Cohnheim, confirmed by Hall (see references in Levene and Meyer's paper, 1911), showed that, while the addition of muscle plasma or of pancreatic extract to solutions of glucose had practically no effect in causing fall in copper-reducing power, mixtures of the two had a considerable effect. The conclusion was naturally drawn that the effect of the pancreas was to facilitate the consumption of glucose by the muscles. But Levene and Meyer (1911) found that the reducing power of such sugar solutions after action of combined muscle and pancreas extracts was restored to its original height by boiling with 1 per cent, hydrochloric acid. Further, the apparent disappearance was only to be obtained with concentrated glucose solutions. If the product of the action of the combined extracts was diluted ten times and allowed to stand, the original reducing power returned. It was evident, therefore, that the effect was due to the activation of some enzyme system, which acts, as usual, in a synthetic manner on glucose, in a hydrolytic manner on the disaccharide formed in concentrated solutions of glucose. Further experiments showed that dilute solutions of maltose were hydrolysed by the mixture, whereas it was shown later (1912) that lactose was not so hydrolysed, and that synthesis occurred neither with mannose, xylose, ribose, nor galactose, but that it did with fructose. The experiments, interesting in themselves, show that the phenomenon has nothing to do with diabetes.

The next point that comes up for discussion is the origin of the hormone, since there are two different tissues in the pancreas, the cells which secrete the digestive juice and the structures called the " islets of Langer harts." Although it had been suggested that these latter are the organs which secrete the antidiabetic hormone, certain observers had advocated the view that they do not constitute a tissue sui generis, but are produced from the ordinary alveoli of the gland. The question was finally decided by the work of Homans (1912). The results of Bensley, showing that the islets could be stained selectively, both after fixation and by intravital injection of methylene blue, neutral red, or pyronin, were first confirmed, so that it was possible to detect changes in the size or number of the islets. If the gland is excited to prolonged activity with secretin, no change in the islets can be detected. If only a small part of the gland is left in an animal, no conversion of acinous tissue to islet tissue occurs, as might be expected to happen if it were possible. Previous investigators had found that the pancreas, by injection of paraffin into the ducts and so on, could be reduced to a state in which no normal acinous tissue could be found, although the islets remained and no diabetes occurred. Homans points out, however, that the decisive proof of the connection of the islets with carbohydrate metabolism is not hereby given unless it is shown that the remains of the gland acini play no part and could be removed without diabetes occurring. At the same time, evidence distinctly points to the islets as the responsible tissue. Fig. 257 reproduces three of those given by Homans.

Interrelation of Internal Secretions. — Various statements have been made as to the mutual relation of these organs, especially by Eppinger, Falta, and Rudinger, •who have based elaborate theories on very slender evidence. Elliott (1913, p. 320) justly warns against building on insecure foundations, saying, " Medicine owes no debt of gratitude to those who teach to her theories without proof." Nevertheless, as Elliott himself (1913) points out, there are common features which suggest a common bond : —

(1) Carbohydrate metabolism is influenced, not only by the pancreas, but also by the thyroid in superactivity, in acromegaly, and by the injection of adrenaline. (2) Growth is affected by the testis and the cortex of the suprarenals, arrested by absence of the thyroid. (4) The pituitary becomes hypertrophied when the thyroid is removed. Acromegaly may lead to enlargement of the thyroid. (5) Gaskell (1908, p. 430), on morphological grounds, classifies together the suprarenal cortex, the pituitary, and the thyroid as being modified from the coxal glands, the primitive excretory organs of the ancestral arthropod.

Hormones in Plants. — Although there is no such effective way of chemical interchange in plants as there is in the circulating blood of animals, there is distinct evidence that chemical products of one part are able to influence the activities of other parts. The lateral roots, which normally grow horizontally, can be made to grow vertically downwards if the main root is removed. Errera (190t) investigated, in pines, the corresponding change of direction of growth of a branch into a vertical stem when the apical bud of the main stem is removed. He suggested that the apical bud of the main stem forms some kind of an internal secretion, which prevents the upward growth of the lateral shoots as long as this apical bud is present.

Keeble (1910, pp. 135-137) considers that such "chemical stimulators" play a part in the transfer of the activity of localised cambium cells to others in their neighbourhood. In the case of Convoluta Roscoffensis, the signal for the commencement of the later phases of development owes its origin to the presence of the green algal cells, without whose concurrence, probably by the production of a hormone, no kind of artificial feeding has been found to be effective.