REVIEW ARTICLE. possibly small quantities of other related compounds. It is interesting. University of Edinburgh.

Transcription

1 REVIEW ARTICLE THE ROLE OF THE ADRENAL GLAND IN HOMEOSTASIS.' By MARTHE VOGT. From the Department of Pharmacology, University of Edinburgh. THE adrenal gland has a large share in maintaining the constancy of what Claude Bernard [1865] has called the "milieu interieur", serious disturbances of which lead to disease or death of the warm-blooded organism. One way of studying this share is to determine the conditions which call forth accelerated activity on the part of the gland, and to examine how an animal lacking adrenal hormones fares in the same conditions. Since the adrenal gland consists of two parts, cortex and medulla, this discussion will first deal with the role played by each of these parts singly, and then with the interaction of the two parts in "homeostasis" [Cannon, 1932]. As an introduction, it will be necessary to recall the differences which exist between adrenal cortex and adrenal medulla in the chemical constitution and quantity of the products they secrete, the way secretion is initiated, and the actions of the liberated hormones. NATURE OF HORMONES The adrenal medulla secretes simple aromatic amines, now considered to consist of a mixture of adrenaline and noradrenaline with possibly small quantities of other related compounds. It is interesting to remember that adrenaline was the first hormone to be chemically isolated in crystalline form [Takamine, 1901], and that it came rather as a shock when, forty-eight years later, it was discovered [Goldenberg, Faber, Alston and Chargaff, 1949] that adrenal medullary extracts, supposed to contain only one well-known active principle, namely adrenaline, contained about per cent of a second active compound, noradrenaline. We now know that in all species the medulla secretes a mixture of adrenaline and the simpler nor-compound. 1 Based on a Lecture given in the Department of Physiology, University of Edinburgh. VOL. XXXIX, NO

2 246 Vogt We know that the relative proportion of the two amines varies with the species, the rabbit, for instance, secreting nearly pure adrenaline, and the whale a mixture of which 65 per cent is noradrenaline. In the cat, more than in other laboratory animals, the composition varies greatly between individuals-a fact which makes it difficult to decide whether noradrenaline is a hormone in its own right released for special purposes, or just an "imperfect" form of adrenaline. Some authors incline to the first view, and Redgate and Gellhorn [1953] and von Euler and Folkow [1953 a] are of the opinion that the two amines are released independently by stimulation of different hypothalamic centres. Von Euler and Folkow [1953 b] also reported a different ratio of the two amines when the medulla is stimulated by different means. It is not quite clear, however, whether this shift in the ratio is caused by a change in the quality of the stimulus. It may also be explained by assuming that, the stronger the stimulus, the more adrenaline predominates in the secreted product. Though the role of noradrenaline as a medullary hormone is still obscure, there is no doubt that it is the main component of what is now often called "sympathin", that is, the transmitter released from the postganglionic sympathetic fibres. Here it is the role of the very small quantities of adrenaline which are released along with the noradrenaline [Peart, 1949], which constitutes the problem. It is not likely that the two amines are simply interchangeable, since their physiological actions differ appreciably: thus noradrenaline is the more active compound on the cardiovascular system, whereas its metabolic effects (increase in oxygen consumption, glycogenolysis, release of A.C.T.H.) are much weaker than those of equal amounts of adrenaline. The chemistry of the products of the adrenal cortex is more complex than that of the medullary hormones, the cortical steroids being both larger molecules and very numerous. Fortunately, however, among the compounds found in adrenal vein blood, a few predominate so much that, as a first approximation, they may be considered to be responsible for the effects produced. They are, first, corticosterone and its 17-hydroxy-derivative, now usually called hydrocortisone. It is the lack of these substances which is fatal to the adrenalectomized organism, and an adrenalectomized human being can be satisfactorily maintained with hydrocortisone alone. The relative proportion of corticosterone and hydrocortisone elaborated by the cortex of different species varies greatly-the rat and the rabbit, for example, "live " essentially on corticosterone, whereas the guinea-pig and man sustain their metabolic processes mainly on hydrocortisone. The differences between the actions of the two compounds are only quantitative, hydrocortisone being more active in most though not in all respects. Another substance produced by the adrenal cortex is the newly discovered aldosterone [Simpson, Tait, Wettstein et al., 1954], previously called "electrocortin", a substance which causes sodium retention in

3 The Adrenal Gland and Homeostasis very small amounts indeed; according to certain tests, it is 100 times more active than the most potent previously known sodium-retaining steroid desoxycorticosterone. The concentration of that substance in the blood is less than 1 per cent of that of hydrocortisone, but, owing to its great activity, it appears to have an important share in the part played by the adrenal cortex in mineral metabolism. It is also thought to be responsible for the great life-maintaining activity of the so-called " amorphous fraction " of cortical extracts, a residue left in the preparation of cortical steroids from the adrenal glands of cattle which has baffled the skill of organic chemists for many years. It does maintain life in the Addisonian patient, but appears normally not to be secreted in quantities which would be sufficient for survival, and particularly does not appear to be produced in increased quantities in response to the stimulation of the anterior pituitary by stress (see below). Finally, a word about the androgens known to be elaborated by the adrenal cortex. Little is known about their function, and even less about the question whether they take part in the countermeasures which help to keep up the milieu interieur when its constancy is threatened by adverse conditions. It is likely that their importance lies in the influence androgens generally exert on protein anabolism, and possible that this role is particularly important during foetal development. MODE OF ACTION. 247 The differences between adrenal cortex and adrenal medulla are not confined to the nature of their secretory products. There are contrasts in their mode of activation; thus the adrenal medulla.secretes only when the splanchnic nerves are stimulated, and denervation results in a fall in secretory activity to very nearly zero, except when severe asphyxia causes some hormone to be released into the blood (in the innervated gland the quantities of hormone secreted in asphyxia are very much larger). There is thus a spasmodic activity of the adrenal medulla when the splanchnic nerves are thrown into action; if splanchnic activity is prolonged, the stores of medullary hormone, as first shown by Elliott [1912], may be seriously depleted. Though the adrenal medulla contains stores of hormone which are sufficient to sustain maximal secretion for several hours, resynthesis appears to be slow and to depend, for restoration of the hormone content to normal, on an adequate uptake of aminoacids in the food [van Arman, 1951]. Not so the adrenal cortex. Its stores would supply even resting secretory activity only for 5 to 20 seconds [Vogt, 1943]; it is probably devoid of secretory nerves; the few fibres ending in the cortex are considered to be vasomotor. Synthetic activity is continuous and keeps pace with the outpour of hormones. It is accelerated by chemical

4 248 Vogt stimuli supplied largely by the anterior lobe of the pituitary (see below), and nervous stimuli are inactive unless they influence the pituitary. One more difference between the actions of cortical and medullary hormones is of great practical consequence, and that is the fact that the hormones of the medulla are highly "pharmacodynamic", acting speedily on smooth muscle, glands, and certain rapid metabolic processes like glycogenolysis, whereas adrenal corticoids, though they influence metabolic processes in all tissues, do this so surreptitiously that their detection by biological assay on isolated organs has so far not met with the slightest success. This is the reason why it is possible to measure, with the help of biological assays, normal blood concentrations of adrenaline although they are of the order of 0.1 ug/l., whereas the blood concentrations of hydrocortisone, which are 1000 times as large, are more difficult to detect and have to be measured by rather unspecific chemical methods. CONDITIONS WHICH STIMULATE THE ACTIVITY OF THE ADRENAL GLAND. It is to Elliott [1912] and Cannon [Review, 1932] we owe much of the knowledge of the natural circumstances which lead to secretion of adrenaline and thus to the role played by the adrenal medulla in what, following Cannon's suggestion, we often call "homeostasis". Cannon emphasized that adrenaline is released under certain conditions of "stress", and thus introduced into adrenal physiology the word which has since become so familiar through its use by Selye in adrenal cortical physiology. As an example of medullary stimulation as a countermeasure in stress, let us consider the changes occurring in a mammal in flight before a foe. It is easy to see that the muscular effort demanded of the fleeing animal will be favoured by many of the physiological actions of the outpouring adrenaline, such as the increase in the force of the heart beat, the redistribution of the blood, the contraction of the spleen, the rise in blood sugar, and the arrest of intestinal movement. The usefulness of the adrenaline secretion is borne out by the observation that animals which have been subjected to adrenal denervation fatigue more readily during muscular effort. Strenuous muscular exercise is only one of many conditions calling forth, and benefited by, secretion of medullary amines; other wellknown examples are sudden haemorrhage, rapid change in environmental temperature, oxygen lack, hypoglyceemia and emotion, most of which are poorly withstood if the adrenals have been denervated and the medulla is thus prevented from responding. Such animals are, however, less incapacitated than one might expect, and it needs the additional removal of the adre% cortex so to impair the adaptability of the organism as to cause seriotf debility and death.

5 The Adrenal Gland and Homeostasis After complete adrenalectomy no organ functions optimally: the muscles tire, the blood pressure falls, the electrolyte distribution is abnormal, the kidneys do not excrete salt or water loads adequately, the blood vessels do not maintain their tone under the influence of impulses from the vasoconstrictor nerves or when exogenous noradrenaline is administered [Levine, 1952]. The animal lacking adrenal cortices exhibits ubiquitous metabolic disturbances which, without arresting any function completely, impair all organ activity sufficiently to render extra work and thus countermeasures against any stress difficult, slow or impossible. A list of conditions leading to accelerated cortical secretion includes all those which cause medullary secretion but, in addition, contains numerous stimuli to which the adrenal medulla fails to respond, such as infectious diseases, malnutrition, pregnancy, and the action of many drugs. All these conditions of "stress" have in common that some, and sometimes many, organs are called upon to carry out more work than in the resting condition. From this definition it follows that their number is almost unlimited. AIECHANISMS RESPONSIBLE FOR ADRENAL STIMULATION. 249 The activation of the adrenal medulla always follows the same pattern: a reflex is elicited by the adverse conditions and leads to the stimulation of central, usually hypothalamic structures which, in turn, send efferent impulses into the splanchnic nerves. A similar pathway to the adrenal cortex is lacking. How, then, is it called into action? The answer is provided by observations in the hypophysectomized animal. After hypophysectomy, the adrenal cortices remain active, but they secrete at a slow, steady rate and fail to respond to stress. It is the lack of adrenocorticotrophic hormone or "A.C.T.H.", elaborated in the anterior lobe, which is responsible for the failure of the adrenal cortex to vary its secretion according to the requirements of the body. The question, therefore, of how the adrenal cortex responds to increased demands by increased secretion, becomes transformed into the question why the anterior pituitary increases the release of A.C.T.H. during stress. One mode of stimulation is provided by the anterior lobetarget organ relationship known also to exist for other glands controlled by the anterior lobe, such as the thyroid and the gonads. A high level of circulating hormone from the target organ, in this case the adrenal cortex, depresses secretion of the trophic hormone, and a low level acts as a stimulus. This hypothesis, which was put forward by Sayers and Sayers [1945], is based on good experimental evidence. Administration of cortical steroids in excess of the needs of the organism inhibits cortical secretion by inhibiting release of A.C.T.H., and total lack of endogenous corticoids, as it occurs after adrenalectomny, leads to

6 250 Vogt abnormally high blood values of A.C.T.H. It is, however, doubtful whether the same mechanism will explain the fine adjustment of A.C.T.H. secretion in less extreme circumstances. Another possibility was suggested by the observation that, whenever the adrenal medulla is called into action, the adrenal cortex is stimulated as well. This fact was first suspected by Sj6strand [1934], who observed that hyperaemia of the adrenal cortex occurred whenever the adrenal medulla was active. This correlation has since been firmly established by more direct measurements of cortical activity. Not only, however, does cortical secretion always accompany medullary secretion, but the two are often causally related: thus it has been shown that in the dog or in the rat, adrenaline administration causes a release of A.C.T.H. and thus accelerates cortical secretion. We may therefore well ask whether the organism depends on adrenaline for the release of A.C.T.H. in those types of stress in which the medulla is secreting. The answer is given by exposing animals which have been deprived of their adrenal medullae to such forms of stress and measuring the respone of the adrenal cortex. The answer is that A.C.T.H. is still being released by a stress which, like hypoglycaemia, normally activates both parts of the adrenal gland. Thus, in spite of the fact that, normally, adrenaline contributes to the release of A.C.T.H. in hypoglycoemia, the organism does not depend on this mechanism in order to call the adrenal cortex into action. This is a very typical example of a general biological phenomenon which only too often defeats the experimenter who hopes to carry out a "crucial" experiment. The organism usually has more than one way of achieving an important aim, and if the experimenter blocks one of them, the defect may be hardly noticeable because the alternative way is perfectly adequate to deal with the body's needs. There is, however, one form of stress, emotional stress, in which adrenaline secretion is the main cause of cortical activation. Even a very slight emotion, like the exposure of a rat to an unaccustomed situation, elicits secretion by the adrenal medulla and by the adrenal cortex. If the adrenals are demedullated, the response of the adrenal cortex is greatly diminished. This proves that, in contrast to the situation encountered in hypoglyceamia, adreno-cortical activity in emotion is largely the result of adrenaline secretion. That there is a residual cortical response after demedullation, however, shows that even here the situation is complex. Appreciable metabolic changes, such as prevail in the majority of conditions of " stress ", can hardly be expected to accompany the emotional response to an unaccustomed situation; hence direct stimulation of the anterior lobe by abnormal metabolites (see below) is extremely unlikely. The probable explanation is that the conditions leading to the emotional response affect the hypothalamus, and that hypothalamic structures activate the release of A.C.T.H. from the anterior lobe.

7 The Adrenal Gland and Homeostasis 251 SITE OF "RECEPTORS" WHICH RESPOND TO STRESS. This leads us to the question of the site of the "receptors" which respond to a stress by initiating A.C.T.H. secretion. Some authors assume that they lie in the pituitary tissue itself, and support this theory by the results of experiments in which transplanted pituitaries have been shown to discharge A.C.T.H. in response to administration of adrenaline or histamine. Such activation of the pituitary would then be entirely humoral. Any agent, such as a metabolite or foreign substance circulating in the blood, might thus elicit the release of A.C.T.H. from the pituitary tissue itself. This release might be either a direct response to the agent or a consequence of a fall in the level of circulating cortical hormone caused by that agent. Other observations, however, point to additional possibilities [Fortier, 1951]. Thus the response to, at least, certain forms of stress is abolished by producing bilateral lesions in the hypothalamus [de Groot and Harris, 1950], so that the receptors activated under these conditions lie in the central nervous system, which is found to exert some control over the anterior lobe. Since there is no nervous link between hypothalamus and anterior lobe of the pituitary, this hypothalamic control must be effected by a humoral mechanism in which the so-called "portal" vessels of the pituitary are supposed to transmit some chemical agent. Its nature is the subject of much speculation and research. SYNERGISM BETWEEN ADRENAL CORTEX AND MEDULLA. Not only is the cortex always stimulated when the medulla is secreting, but there are other aspects of medullary-cortical relationships which are worth discussing. There often is synergism between the hormones originating from the two parts of the gland. For instance, they both counteract hypoglycaemia, they both protect from damage by histamine, they both have certain anti-inflammatory effects. These ends are, however, achieved by different means. There also exists a type of synergism which is based on potentiation, by certain corticosteroids, of the actions of medullary hormones. Levine [1952] and his co-workers have demonstrated that the vasoconstrictor effect of noradrenaline is onlv maintained in the presence of cortisone and allied compounds. This synergism is not confined to the vascular actions of noradrenaline; it has also been found for the fat-mobilising effect of adrenaline and for its glycogenolytic action. This last phenomenon is similar to that originally demonstrated by Otto Loewi [Fluch, Greiner and Loewi, 1935] in the hypophysectomized frog, and probably caused in this preparation by lack of A.C.T.H.

8 252 The Adrenal Gland and Homeostasis For an understanding of the fundamental action of cortical hormones in the tissues, it is of some interest to consider whether irresponsiveness to the sympathomimetic amines of tissues lacking in corticoids is not simply an example of what Ingle [1952] has called the "permissive action" of cortical hormones. This term refers to the fact that many, perhaps all, of the deficiencies which occur in the adrenalectomized animal are of a peculiar type. They are not immediate consequences of the lack of steroids in the sense that, say, a muscle ceases to contract if there is no acetylcholine liberated at its end-plate. The corticoids bestow on the tissues the capacity to react efficiently to internal or environmental stimuli but are not themselves these stimuli. In our special case, cortical hormones appear to "permit " the response of different tissues to the stimulating action of medullary amines. REFERENCES. VAN ARMAN, C. G. (1951). Amer. J. Physiol. 164, 476. BERNARD, CLAUDE (1865). Introduction a l'etude de la medecine experimentale, p Paris. CANNON, W. B. (1932). The Wisdom of the Body. London. Kegan Paul. ELLIOTT, T. R. (1912). J. Physiol. 44, 374. VON EULER, U. S., and FoLuow, B. (1953 a). Abstr. XIX int. physiol. Congr., 357. VON EULER, U. S., and FOLKOW, B. (1953 b). Arch. exp. Path. Pharmak. 219, 242. FLUCH, M., GREINER, H., and LOEWI, 0. (1935). Arch. exp. Path. Pharmak. 177, 167. FORTIER, C. (1951). Endocrinology, 49, 782. GOLDENBERG, M., FABER, M., ALSTON, E. J., and CHARGAFF, E. C. (1949). Science, 109, 534. DE GROOT, J., and HARRIS, G. W. (1950). J. Physiol. 111, 335. INGLE, D. J. (1952). J. Endocr. 8, 23 P. LEVINE, R. (1952). Bull. Schweiz. Akad. Wiss. 8, 13. PEART, W. S. (1949). J. Physiol. 108, 491. REDGATE, E. S., and GELLHORN, E. (1953). Amer. J. Physiol. 174, 475. SAYERS, G., and SAYERS, M. A. (1945). Proc. Soc. exp. Biol. N. Y. 60, 162. SIMPSON, S. A., TAIT, J. F., WETTSTEIN, A., NEHER, R., EUw, J. V., SCHINDLER, O., and REICHSTEiN, T. (1954). Experientia 10, 132. SJdSTRAND, T. (1934). Skand. Arch. Physiol. 71, 85. TAKAMINE, J. (1901). J. Physiol. 27, 29 P. VOGT, M. (1943). J. Physiol. 102, 341.