Uninephrectomized rats drinking 1% sodium chloride were given aldosterone (Aldo, 0.75 gg/h, subcutaneous Is.c.I infusion), deoxycorticosterone (DOC, 20 mg/wk, s.c.), corticosterone (B, 2 mg/d, s.c.), or the antiglucocorticoid-antiprogestin RU486 (2 mg/d, s.c.) for 8 wk, and hemodynamic and tissue responses were compared with a non-steroid-treated control group. Aldo and DOC markedly increased systolic BP and caused considerable (40-50%) cardiac hypertrophy; B and RU486 caused neither hypertension nor cardiac hypertrophy. Measurements of ventricular cross-sectional areas showed hypertrophy due to an increase in mass of the left ventricle only. Cardiac hydroxyproline concentration was increased considerably by Aldo and DOC, to a lesser degree by RU486, and not by B. Aldo markedly elevated left ventricular interstitial collagen (2.5-fold vs control, P < 0.01 vs all groups); other steroid treatments also increased interstitial collagen over control (DOC X 1.8-, RU486 X 1.6-, B X 13-fold), with identical responses for right and left ventricles (r = 0.94). A different pattern of perivascular fibrosis was noted; DOC elevated perivascular collagen (2.1-fold vs control, P < 0.01 vs all other groups); RU486 raised levels 1.4-fold vs control, but neither Aldo nor B significantly affected perivascular collagen. These data are consistent with interstitial cardiac fibrosis reflecting type I (mineralocorticoid) receptor occupancy by administered Aldo or DOC, or by elevated endogenous B after type II (glucocorticoid) receptor blockade after RU486 administration; perivascular fibrosis may reflect a composite response after type I receptor agonist/type II glucocorticoid receptor antagonist occupancy. (J. Clin. Invest. 1994.93:2578-2583

Studies were undertaken to characterize the secretion of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) into the hypophysial-portal circulation of the conscious sheep. In addition, we examined the temporal relationship between the secretion of these two hypothalamic peptides and the secretion of three pro-opiomelanocortin peptides – adrenocorticotropic hormone (ACTH), ir-β-endorphin, and ir-α-melanocyte-stimulating hormone – and cortisol and determined the effects of an audiovisual emotional stimulus and insulin-induced hypoglycemia on the entire hypothalamic-pituitary-adrenal axis. In the basal state, the secretion of CRF, AVP, the three pro-opiomelanocortin peptides, and cortisol was pulsatile in nature, and three CRF and AVP pulse patterns were observed: a concordant increase in CRF and AVP, an isolated rise in CRF, and an isolated increase in AVP. In 4 of the 5 animals, a 3-min audiovisual stress (barking dog) rapidly increased the plasma levels of all the measured substances, although the magnitude and duration of the effect differed markedly between the animals. Insulin-induced hypoglycemia markedly increased AVP and, to a lesser extent, CRF concentrations in portal plasma and thereby altered the CRF:AVP molar ratio. Although pituitary-adrenal activation was closely correlated with the increased hypothalamic activity, a strict 1:1 concordance between CRF/AVP secretion and ACTH secretion was not seen. The anesthetic ketamine selectively increased portal AVP concentrations to levels which exceeded those attained during hypoglycemia and rapidly activated the pituitary-adrenal axis. We conclude the following: (1) CRF and AVP are secreted by the hypothalamus in a pulsatile fashion; (2) ACTH secretion can be stimulated by increases in either CRF or AVP; (3) the absence of a strict 1:1 concordance between hypothalamic CRF/AVP release and pituitary ACTH secretion during stress may be partly due to the release of additional hypothalamic ACTH secretagogues; (4) the ability of both audiovisual stimuli and insulin-induced hypoglycemia to augment CRF and AVP secretion indicates that the paraventricular hypothalamus may be activated by a variety of neural inputs, and (5) the marked alteration of the CRF:AVP molar ratio during stress suggests that AVP may be an important ACTH secretagogue in vivo in the sheep.

Aldosterone does not exert a direct effect on collagen synthesis in rat cardiac fibroblasts grown in culture. The increased cardiac collagen observed in vivo in aldosterone treated, salt loaded rats may thus represent secondary effects of aldosterone in this model.

Genomic mechanisms of steroid action have been increasingly elucidated over the past four decades. In contrast, rapid steroid actions have been widely recognized only recently, and detailed analysis of the mechanisms involved are still lacking. The present article describes rapid effects of mineralocorticoid hormones on free intracellular calcium in vascular smooth muscle cells as determined by fura 2 spectrofluorometry in single cultured cells from rat aorta. These effects are almost immediate and reach a plateau after only 3 to 5 minutes and are characterized by high specificity for mineralocorticoids versus glucocorticoids. The potent mineralocorticoids aldosterone and fludrocortisone are agonists with estimated apparent EC50 values of approximately 0.1 to 0.5 nmol/L; deoxycorticosterone acetate is an agonist with an EC50 of approximately 5 nmol/L; and progesterone, cortisol, corticosterone, and estradiol have much lower potency (EC50 values of approximately 0.5 to 5 mumol/L). The effect of aldosterone is blocked by neomycin and short-term treatment with phorbol esters but augmented by staurosporine, indicating an involvement of phospholipase C and protein kinase C. The Ca2+ effect appears to involve the release of intracellular Ca2+, as shown by the inhibitory effect of thapsigargin; intriguingly, a relatively small maximum effect (approximately 40 nmol/L increase) is consistently seen. This mechanism operates at physiological subnanomolar aldosterone concentrations and appears to be a likely candidate for rapid fine tuning of cardiovascular responsivity. It may also contribute to known clinical features of mineralocorticoid action that are difficult to explain by the traditional genomic mechanism alone.

No abstract