Aldosterone specific membrane receptors, rapid activation of the sodium-hydrogen exchanger, and cardiovascular implications

Abstract

Functional studies in extrarenal non-epithelial cells such as smooth muscle cells and easily accessible human lymphocytes have demonstrated that aldosterone not only produces classical genomic effects, but also rapid non-genomic effects on transmembrane electrolyte movements. These involve the activation of the Na⁺/H⁺ exchanger of the cell membrane at very low, physiological concentrations of aldosterone with an acute onset within one to two minutes. They cannot therefore be explained by genomic mechanisms which appear to succeed the membrane related rapid responses as late effects. The mechanisms underlying these fast aldosterone electrolyte effects have been studied extensively in human lymphocytes and rat vascular smooth muscle cells representing attractively valuable tools in the delineation of the receptor-effector mechanisms involved. This includes the demonstration of membrane binding sites in lymphocytes which are highly specific for aldosterone and transmit the rapid non-genomic responses to aldosterone, as suggested by the intriguing similarities of binding kinetics and pharmacology in the receptor and effector assays. The unique characteristics of this new pathway for steroid action includes its rapid time course, 10000-fold selectivity for aldosterone over cortisol, and the ineffectiveness of spironolactones, the classical mineralocorticoid antagonists. The two step model for the membrane action of mineralocorticoids developed here shares many features with that developed for other steroid hormones, for example on their neural activity. Since not only lymphocytes but also vascular smooth muscle cells are equipped with the rapid aldosterone effector mechanism, this new model may become the basis for the developing concept of steroids as regulators of cardiovascular functions.