The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

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How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Contemporary findings reveal that the multiple modes of autonomic control do not lie along a single continuum extending from parasympathetic to sympathetic dominance but rather distribute within a 2-dimensional space. The physiological origins and empirical documentation for the multiple modes of autonomic control are considered. Then a formal 2-dimensional conception of autonomic space is proposed, and a quantitative model for its translation into a functional output surface is derived. It is shown that this model (a) accounts for much of the error variance that has traditionally plagued psychophysiological studies, (b) subsumes psychophysiological principles such as the law of initial values, (c) gives rise to formal laws of autonomic constraint, and (d) has fundamental implications for the direction and interpretation of a wide array of psychophysiological studies.

Autonomic determinism: the modes of autonomic control, the doctrine of autonomic space, and the laws of autonomic constraint.

Interactions Between Cardiovascular and Pain Regulatory Systems

The supraspinal afferent and efferent connections of the A5 noradrenergic cell group were examined in rats. Very small deposits of HRP-WGA were made in the rostral A5 area. Catecholamine histofluorescence techniques were used to confirm that the deposits overlapped the A5 column. Retrogradely labeled cells were present in the perifornical area and paraventricular nucleus of the hypothalamus, the Kolliker-Fuse nucleus, dorsal parabrachial area, intermediate and caudal portions of the nucleus of the solitary tract, and the ventral medullary reticular formation in the areas of the A1 and B1 cell groups. Anterograde HRP-WGA labeling was found in several areas of the subcortical CNS. The contribution of A5 neurons to this labeling was confirmed with retrogradely transported fluorescent latex microspheres combined with catecholamine histofluorescence techniques. The A5 cell group was found to have significant projections to the central nucleus of the amygdala, perifornical area of the hypothalamus, midbrain periaqueductal gray, parabrachial area, and the nucleus of the solitary tract. Other A5 projections include the paraventricular nucleus of the thalamus, the bed nucleus of the stria terminalis, and possibly the zona incerta and lateral and dorsal hypothalamic areas. In addition, A5 neurons may innervate the ventrolateral reticular formation of the medulla. Virtually all of the areas innervated by A5 noradrenergic neurons are involved in cardiovascular regulation. In addition, the A5 area receives afferent input from major cardiovascular regulatory centers of the supraspinal CNS. Thus the A5 cell group has the potential to exert a significant influence on the cardiovascular regulatory system.

Afferent and efferent connections of the A5 noradrenergic cell group in the rat.

Cellular localization and possible functions for brain histamine: recent progress.

Neurophysiology and neuropharmacology of cardiovascular regulation and stress

Calcium and vitamin D metabolism were evaluated in 5 adult epileptic patients before and during treatment with phenytoin. Significant decreases occurred in serum concentrations of calcium, albumin, and 25-hydroxy-cholecalciferol. The decreases in serum calcium paralleled those in serum albumin. Significant increases occurred in serum alkaline phosphatase and 1 alpha, 25-dihydroxycholecalciferol, in urinary hydroxyproline, and in the fractional gastrointestinal absorption of calcium. Urinary cyclic adenosine monophosphate and serum parathyroid hormone did not change. The results suggest that the bone disease resulting from phenytoin therapy may be associated with a deficiency of 25-hydroxycholecalciferol and not of 1 alpha, 25-dihydroxycholecalciferol, and that reduced gastrointestinal absorption of calcium or changes in parathyroid function may not be necessary for the development of bone disease.

Effect of phenytoin on bone and vitamin D metabolism

An increasing number of clinical studies address interactions of cardiovascular drugs in terms of both their importance in the treatment of disease and their potential to cause drug-induced toxicity. Several books and reviews are devoted to extensive listings of both observed and theoretical drug interactions [1–4]. Such listings often include extrapolation of animal data, anecdotal case reports, and interactions of questionable importance. Consequently, their literal use could result in withholding therapy or overcomplicating therapeutic decisions. Some drug interactions are critical for optimum patient care, such as combined use of drugs for their additive or synergistic effects, while others, although academically interesting, have little clinical relevance. In this review, it is not our intent to provide extensive listings of cardiovascular drug interactions but to use clinical examples to illustrate pharmacological principles which may then be extrapolated to individual patients [5].

Michael Vasko

Papers

Neurophysiology and neuropharmacology of cardiovascular regulation and stress

Effect of phenytoin on bone and vitamin D metabolism

Update of cardiovascular drug interactions