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Steroids. 2005 May-Jun;70(5-7):347-51. Epub 2005 Mar 24.

Nongenomic effects of mineralocorticoid receptor activation in the cardiovascular system.

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Department of Cardiology, Royal North Shore Hospital, University of Sydney, Sydney 2065, Australia.


Fifteen years ago Wehling and colleagues showed unequivocal rapid effects of aldosterone, neither mimicked by cortisol nor blocked by spironolactone, and postulated that these nongenomic effects are mediated via a membrane receptor distinct from the classical mineralocorticoid receptor (MR). Several recent studies have challenged this view. Alzamora et al. showed 11beta-hydroxysteroid denydrogenase 1 and 2 (11betaHSD1, 11betaHSD2) expression in human vascular smooth muscle cells, and that aldosterone rapidly raises intracellular pH via sodium-hydrogen exchange; cortisol is without effect and spironolactone does not block the aldosterone response. When, however, 11betaHSD activity is blocked by carbenoxolone, cortisol shows agonist effects indistinguishable from aldosterone; in addition, the effect of both aldosterone and cortisol is blocked by the open E-ring, water soluble MR antagonist RU28318. In rabbit cardiomyocytes, aldosterone increases intracellular [Na+] by activating Na+/K+/2Cl- cotransport, with secondary effects on Na+/K+ pump activity. Pump current rises approximately 10-fold within 15', is unaffected by actinomycin D or the MR antagonist canrenone, and not elevated by cortisol. Pump current is, however, completely blocked by the open E-ring, water soluble MR antagonist K+ canrenoate and stoichometrically by cortisol. PKCepsilon agonist peptides (but not PKCalpha, PKCdelta or scrambled PKCepsilon peptides) mimic the effect of aldosterone, and PKCepsilon antagonist peptides block the effect. Very recently, cortisol has been shown to mimic the effect of aldosterone when cardiomyocyte redox state is altered by the installation of oxidized glutathione (GSSG) via the pipet, paralleling the effect of carbenoxolone on vascular smooth cells and suggesting possible pathophysiologic roles for an always glucocorticoid occupied MR.

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