A Unified Theory of Glucocorticoid Action

A UNIFIED THEORY OF GLUCOCORTICOID ACTION RICHARD W. SCHAYER, Ph.D.* In this essay an attempt will be made to relate the major observations on the physiology and pharmacology ofthe adrenal glucocorticoid hormones to a single primary event—passive attachment ofhormone molecules to microvascular smooth-muscle cells and consequent interference with the autonomous dilator activity ofthe small blood vessels. The microcirculation can dilate in response to various stimuli through a mechanism which is independent of any form of systemic control [1-3] and which appears to be intrinsic. Ifcertain ofthese autonomous dilator responses are mediated by a single mechanism, a unity in glucocorticoid effects becomes discernible, for from the postulated antagonism between corticoids and the intrinsic dilator may be derived the nonessential nature of glucocorticoids in the resting animal, their essential nature in stress, neutralization of corticoid effects during stress, their apparent duality of action, the variability in their requirement, their pronounced influence on metabolism and cell function, their anti-inflammatory and limited antishock effects, their close functional relationship to catecholamines, and their permissive or supportive role. The present theory arose from recent studies which suggest that histamine is the intrinsic microcirculatory dilator [4-7]. My earlier arguments on glucocorticoid action [6, 7] seem to have been weakened by requiring prior knowledge of a radically new concept of histamine metabolism. Accordingly, for the present argument, it is asked onlythat two reasonable postulates be tentatively accepted. First, the small blood vessels are normally under the continuous influence ofa newly synthesized intrinsic dilator; its rate ofsynthesis is increased by stimuli which create need for augmented * From the Merck Institute for Therapeutic Research, Rahway, NewJersey. Present address'of author: Laboratory ofChemical Pharmacology, National Heart Institute, Bethesda, Maryland. 71 local blood flow. Second, the glucocorticoids can oppose the microcirculatory actions ofthis dilator. Relative to the first postulate, the idea that local products ofmetabolism relax capillary tone dates back at least to 1879 [8]. Dale and Richards [9] first proposed that the dilator, produced continuously under normal conditions but in increased amounts following injury, might be a histaminelike substance. This thesis was developed into an extraordinarily lucid interpretation of microcirculatory behavior by Sir Thomas Lewis [2]. Although many of Lewis' ideas have been rejected, this seems largely attributable to the poor understanding of histamine metabolism which has been prevalent. This postulate is supported bythe arguments ofLewis, who emphasized that responses of small vessels to the mildest stimuli passed gradually to responses sufficiently intense to threaten life, by a simple transition, the differences being only in quantity, not quality. A common pathway to the open capillary beds in inflammation and shock has been stressed by many authors [2, 3, 10]. Regarding the second postulate, it is also a very old idea that circulating vasoconstrictor hormones such as adrenalin and pituitary substances [1, 2] interact with the dilator to influence local blood flow. The vasoconstrictor tendencies of glucocorticoids are established [11-14]. The validity ofthese two basic postulates is well supported by the author's published works [4-^7]. Of the known autonomous dilator phenomena, three are heavily involved in the interpretation of glucocorticoid effects. 1)Vasomotion. This is the periodic dilation and constriction of microcirculatory smooth muscle which governs the opening and closing of capillaries and other small vessels and constitutes the most precise adjustment oflocal blood flow [3]. A possible mechanism by which individual capillaries may open and close independently has been published [7]. 2)Thegradually developing dilator response to local irritation or injury. This response develops after a latent period ofroughly 30-60 minutes and increases gradually, becoming maximalin approximately4to 6 hours. It may persist as long as the stimulus is present. The existence ofthe latent period may be demonstrated in animals pretreated with antihistamines, a procedure which blocks the immediate dilator effects of released mast cell histamine [15]. 3)The gradually developing dilator response to systemic stress. Following any stimulus which releases catecholamines, there is an initial period of 72 Richard W. Schayer · A Unified Theory ofGlucocorticoid Action Perspectives in Biology and Medicine · Autumn 1964 vasoconstriction. This is gradually alleviated by activation ofthe intrinsic dilator mechanism which occurs at essentially the same rate as observed after irritation. The evidence supporting histamine as the...