Stimulation of the adrenal cortex

The evidence in favour of a relationship between non-steroidal antirheumatic activity and the pituitary-adrenal system is based mainly on experiments involving salicylates and phenylbutazone. No attempt will be made to discuss these problems in detail since they have been adequately reviewed by Smith and Done for salicylates, and by Rechenburg for phenylbutazone. Smith argued persuasively that the available experimental evidence on salicylates does not support the view that they either mimic or reinforce the actions of the natural adrenocortical hormones, and that the similar clinical effects of salicylates and these steroids in rheumatic diseases must therefore be produced by different mechanisms. Done, on the other hand, suggests that the concept cannot be prematurely dismissed and believes that the possibility that salicylate simultaneously affects the production and disposition of adrenocortical hormones deserves further consideration. He emphasizes that the antirheumatic effects of salicylates are not dependent on the maintenance of elevated circulating levels of corticoids. 

More recently, a similarity has been noted between urinary electrolyte changes after large doses of salicylate in man and those folio-wing stress or hydrocortisone administration . Further evidence, however, indicates that these findings may not reflect pituitary-adrenal stimulation . Perfusion of the dog adrenal with salicylate does not stimulate hydrocortisone secretion and there is no evidence to indicate that salicylates potentiate the thymolytic action of adrenal corticosteroids . Despite the confusing evidence, it seems doubtful that phenylbutazone influences the pituitary, and any stimulation of the adrenal cortex is probably slight and non-specific . There is, however, some indication that phenylbutazone in vitro inhibits the metabolic inactivation of adrenal steroids . 

Of the more recently introduced antirheumatics, indomethacin is equally active in anti-inflammatory test in intact and adrenalectomized rats , and there is no evidence of adrenal/dependence or corticoid hormone effects for flufenamic acid at non-toxic l6se levels .  

The weight of the evidence seems to suggest that the antirheumatic action of acetylsalicylic acid and phenylbutazone is not mediated through stimulation of the pituitary-adrenal axis. If the inhibition of sulphate uptake by 

Reid and his colleagues put forward the theory that the anti-inflammatory action of salicylate is due to its power to form metal chelate complexes. On this basis, it would be predicted that 2,6-dihydroxybenzoic acid (y-resorcylic acid) would be an even more potent anti-inflammatory agent. As already seen (page 77), early hopes of increased potency of this compound were not fulfilled. Nevertheless, the fact remains that many anti-inflammatory substances form coloured complexes with ferric ions in circumstances in which chemically related but inactive compounds do not . Salicylate, phenylbutazone and cinchophen behave in this way. Wiesel described metal chelate compounds of the anti-inflammatory glucocorticoids and showed that 

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Transient elevations in blood pressure and heart rate occur with seizures, probably as a result of increased sympathetic stimulation that leads to increases in norepinephrine levels. Hypertension or increased pretreatment heart rate are strongly predictive of peak postictal change in both heart rate and blood pressure ( 38). Increased parasympathetic stimulation decreases the heart rate as a result of inhibition of the sinoatrial node. Stimulation of the adrenal cortex leads to increased plasma corticosteroids and stimulation of the adrenal medulla, which may also contribute to increases in blood pressure and heart rate. 

The primary function of AC. TH is the stimulation of the adrenal cortex to produce its hormones, which have already been discussed. This is evideni from the therapeutic effect of administration of ACTH. which is closely similar to that of Ihese hormones, so that if ihe action of only one of them is sought, its administration is preferable, Moreover. ACTH stimulates secretion of the androgenic substances mentioned as produced by the adrenal cortex. 

Cortisol secretion fluctuates widely throughout the day, and single. serum measurements are of little value in clinical practice. There is a marked diurnal rhythm. Dynamic tests of cortisol production involving stimulation of the adrenal cortex by synthetic ACTH. or of stimulation or suppression of the whole HPA axis, form an important part of investigations of adrenocortical hyper- or hypofunction and are discussed on the following pages. 

Exogenously administered glucocorticoids produce a negative feedback inhibition on the production of adrenocorticotropic hormone (ACTH) from the anterior pituitary. This results in a decrease in stimulation of the adrenal cortex and a decrease in the production of cortisol and aldosterone. 

Ascorbic acid has a close relationship to adrenal cortical activity (Chapter 11). Stimulation of the adrenal cortex leads to depletion of ascorbic acid stores in the gland, but even in severe depletion cortical function is maintained. In conditions of stress and after administration of corticotropin, requirement and utilization of ascrobic acid is increased. It has been suggested that ascorbic acid is concerned in the oxidation of a precursor of some adrenal cortical steroid (Chapter 11). Pirani postulated that ascorbic acid may have a nonspecific function related to cellular respiratory activity and metabolic rate. 

The synacthen stimulation test illustrates the principle behind these tests. In normal persons, administration of synacthen (a synthetic form of ACTH) results in stimulation of the adrenal cortex and a subsequent rise in the plasma cortisol level. When there is adrenocortical hypofunction, as in Addison s disease, the rise in the plasma cortisol level doe not occur or is markedly reduced. 

Corticotropin ACTH Pituitary gland. Stimulation of the adrenal cortex... 

The physiological effect of corticotropin consists in the stimulation of the adrenal cortex. The production of corticoid hormones is enhanced, and stored cholesterol is... 

Angiotensin II stimulates aldosterone synthesis and secretion from the glomerulosa cells of the adrenal cortex. The aldosterone secretion induced by angiotensin II in humans is not accompanied by an increase in glucocorticoid plasma levels. Chronic administration of angiotensin II will maintain elevated aldosterone secretion for several days to weeks unless hypokalemia ensues. 

Ang II acts directly on the zona glomerulosa of the adrenal cortex to stimulate aldosterone synthesis and release. At higher concentrations, Ang II also stimulates glucocorticoid synthesis. 

Adrenocorticotropic hormone (Fig. 4) stimulates the cells of the adrenal cortex into the secretion and production of steroid hormones. Conversely, the pituitary secretion of ACTH is inhibited by the adrenal hormones via a feedback mechanism. 

ACTH stimulates the synthesis of steroids by the cells of the adrenal cortex. The steroidogenic action of ACTH is mediated primarily by the intracellular messenger cyclic AMP acting via cyclic AMP-dependent protein kinase. The evidence for this is that (i) ACTH stimulates cyclic AMP production in intact adrenocortical cells and in plasma membrane preparations (ii) cyclic AMP analogues added to adrenocortical cells stimulate steroidogenesis to the same extent as ACTH and (iii) mutant adrenocortical cells with defective cyclic AMP-dependent protein kinase lack stimulation of steroidogenesis by ACTH [2],... 

ACTH is directly anti-mitogenic for adrenocortical cells, but indirectly stimulates the hypertrophy and hyperplasia of the adrenal cortex (reviewed in Ref. 29). Although the mechanism of the indirect stimulation of proliferation of adrenocortical cells by ACTH is not known it appears to be mediated by cyclic AMP [29], A plausible model for this indirect growth stimulation is that ACTH stimulates the growth... 

Rats on a pantothenic acid-free diet show rapid depletion of adrenal corticosteroids, and reduced production of the steroids in isolated adrenal glands in response to stimulation with adrenocorticotrophic hormone (ACTH). This presumably reflects the role of acetyl CoA in the synthesis of steroids deficiency also results in atrophy of the seminiferous mbules of male rats and delayed sexual maturation in females. As deficiency progresses, there is enlargement, then congestion, and finally hemorrhage, of the adrenal cortex. In young animals, but not in adults, pantothenic acid deprivation eventually leads to necrosis of the adrenal cortex. 

Corticotropin stimulates the synthesis of corticosteroids (of which the most important is hydrocortisone) and to a lesser extent of androgens, by the cells of the adrenal cortex. It has only a minor (transient) effect on aldosterone production, which can proceed independently in the absence of corticotropin the cells of the inner cortex atrophy. 

Two neuropeptides, corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) are released from parvoceUular neurons in the hypothalamic PVN to initiate a stress response. The terminal endings of these neurons, located in the median eminence of the hypothalamus, release CRH and AVP into the hypothalamic-hypophysial portal vessel system, where they travel to the anterior pituitary. The two neuropeptides act syn-ergistically on pituitary corticotrophs to activate the synthesis of pro-opiomelanocortin (POMC). This peptide, discussed in detail below, is processed to produce several peptides including adrenocorticotrophic hormone (ACTH), or corticotropin. ACTH released from corticotrophs travels via the bloodstream to act on cells in the zona fasciculata layer of the adrenal cortex, stimulating the synthesis and release of the glucocorticoids, cortisol (in humans) or corticosterone (in rodents). 

Cortisol. Cortisol, secreted by the adrenal cortex in response to adrenocorticotropic hormone (ACTH), stimulates gluconeogenesis and increases the breakdown of protein and fat. Patients with Cushing s syndrome have increased cortisol owing to a tumor or hyperplasia of the adrenal cortex and may become hyperglycemic. In contrast, people with Addisons disease have adrenocortical insufficiency because of destruction or atrophy of the adrenal cortex and may exhibit hypoglycemia. ... 

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