A Unified Theory of Glucocorticoid Action. II: On a Circulatory Basis for the Metabolic Effects of Glucocorticoids

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A UNIFIED THEORY OF GLUCOCORTICOID ACTION. II ONA CIRCULATORY BASIS FOR THE METABOLIC EFFECTS OF GLUCOCORTICOIDS RICHARD W. SCHAYER, Ph.D.* In a previous paper, an attempt was made to relate a number ofmajor observations on glucocorticoid physiology and pharmacology to a primary microcirculatory effect—passive attachment ofhormone molecules to microvascular smooth muscle cells and consequent interference with the autonomous dilator activity ofthe small blood vessels [i]. This interpretation requires two postulates: First, the small vessels are under the continuous influence of a newly synthesized intrinsic dilator; second, the rate ofdilator synthesis is increased by stressful stimuli, either local or systemic. According to this concept, the progressive opening of the microcirculation observed in slowly developing inflammation, or in stress states, is due to an increased rate of synthesis of the same intrinsic dilator which is normally involved in regulating nutritive blood flow. Then glucocorticoid antagonism ofthe increased dilator influence might underlie the anti-inflammatory nature and stress function of these hormones , while antagonism ofthe normal dilator influence might underlie the metabolic effects. The intrinsic dilator concept is derived from studies on histamine [2-4]. However, it is not essential to the development ofthis hypothesis that the identity ofthe intrinsic dilator and histamine be accepted. With its present extension, this theory of glucocorticoid action seems to be compatible with the following general observations: (a) glucocorticoids are not essential for near-normal length oflife, growth, or reproduction ; (b) there are no major metabolic abnormalities in the well-main- * Research Center, Rockland State Hospital, Orangeburg, New York. Study supported by USPHS grant AM 10155-01. 409 tained adrenalectomized animal; (c) glucocorticoids are essential for survival in almost any form of stress; (d) they act locally; they can exert actions which do not depend on any known systemic regulatory mechanism or on any dispensable tissue; (e) their earliest known effect is on the microcirculation; (f) they are anti-inflammatory but have limited antishock properties; (g) they show a close functional relationship to catecholamines ; (h) their role in stress is supportive or permissive; (i) there may be enormous variations in glucocorticoid requirements; (j) many of their effects are neutralized by stress; (k) in a number oftheir effects, diametrically opposite reactions may be produced, the direction depending on the status of the experimental animal; (/) application of stressors to adrenalectomized animals causes changes which appear to be exact opposites of changes caused by administration of glucocorticoids; (m) glucocorticoids cause tissue water to enter the vascular system; (n) they have a catabolic effect in extrahepatic tissues; this action is particularly marked in lymphoid tissues; (o) they have a strong anabolic eifert in liver, causing activation ofa number ofenzymes and increasing many constituents . Most of these generalizations were treated in earlier publications [i, 2, 5]; in only a few cases will there be additional discussion. The primary purpose of this paper is to relate the observed metabolic effects of glucocorticoids to antagonism ofan intrinsic microcirculatory dilator. I. Vasomotion, Local Blood Flow, and Metabolic Effects of Glucocorticoids The precise adjustment of local blood flow to the nutritive needs of cells is accomplished by the periodic unsynchronized opening and closing of the smallest blood vessels. This automatic process, vasomotion, is intrinsic in origin; the nervous system and extrinsic blood-borne substances may modify vasomotion, but they are not required for it [6-8]. It is believed that dilator molecules are continuously synthesized within smooth muscle cells ofprecapillary sphincters. When a sphincter is closed, dilator molecules accumulate intracellularly until the concentration is sufficient to cause relaxation. Blood enters, dilator molecules diffuse from the cell and are washed away, and the intracellular concentration gradually drops. When the dilator level is sufficiently reduced, constrictor forces again predominate, the sphincter closes, and the cycle is completed [4]. Glucocorticoid molecules, by reducing the influence of the dilator on 410 Richard W. Schayer · Theory ofGlucocorticoid Action Perspectives in Biology and Medicine · Spring 1967 smooth muscle cells, increase the time required to accumulate an effective concentration ofdilator. Hence injection ofglucocorticoids into a normal animal lengthens the constrictor phase of vasomotion, that is, sphincters are closed somewhat longer than normally. The constrictor tendency of corticoids has been directly observed in accessible tissues [9-12]. The consequences ofthis initial circulatory...