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Eplerenone Blocks Nongenomic Effects of Aldosterone on the Na⁺/H⁺ Exchanger, Intracellular Ca²⁺ Levels, and Vasoconstriction in Mesenteric Resistance Vessels

Laboratory of Cellular and Molecular Physiology (L.M., A.M.D., C.H., L.L., E.T.M.), Faculty of Medicine, University Los Andes; and FONDAP Center for Molecular Studies of the Cell (S.L.), Faculties of Chemical and Pharmaceutical Sciences and Medicine, University of Chile, 6782468 Santiago, Chile

Address all correspondence and requests for reprints to: Luis Michea, M.D., Ph.D., Faculty of Medicine, University Los Andes, S. Carlos Apoquindo 2200, Las Condes, 6782468 Santiago, Chile. E-mail: lmichea{at}uandes.cl.

There is increasing evidence for rapid nongenomic effects of aldosterone. Aldosterone has been demonstrated to alter intracellular pH and calcium in isolated cells. However, few studies have correlated these effects with aldosterone-mediated physiological responses. Therefore, we studied rapid effects of aldosterone on vascular reactivity, intracellular Ca²⁺, and pH in resistance vessels. Furthermore, we explored whether the new antimineralocorticoid drug eplerenone could effectively block nongenomic aldosterone-mediated effects. The vasoconstrictor action of aldosterone was examined directly by determining the diameter of small resistance mesenteric vessels (160–200 µm resting diameter), simultaneously with intracellular pH or Ca²⁺. Aldosterone (10 nM) caused a rapid constriction of resistance vessels (8.1% ± 1.0% reduction in the diameter below control conditions, P < 0.05). Aldosterone potentiated phenylephrine-mediated constriction in small and large mesenteric vessels. Aldosterone induced a rapid increase of intracellular Ca²⁺ and cellular alkalinization. Vasoconstrictor action of aldosterone and nongenomic effects on the sodium-proton exchanger (NHE1) activity or intracellular Ca²⁺ responses was abolished by eplerenone. The vasoconstrictor response of aldosterone was related to phosphatidylinositol 3-kinase (PI3-K): the hormone decreased protein kinase B phosphorylation; pharmacological inhibition of PI3-K (10 µM LY294002 or 1 µM wortmannin) increased arterial contractility. Inhibitors of ERK 1/2 phosphorylation (15 µM PD98059) had no effect on aldosterone-mediated vasoconstriction. Inhibition of protein kinase C with 1 µM bi-sindolylmaleimide I and/or inhibition of NHE1 with 100 µM amiloride abolished aldosterone vasoconstrictor action of resistance mesenteric arteries. We conclude that aldosterone-mediated increase in vascular tone is related to a nongenomic mechanism that involves protein kinase C, PI3-K, and NHE1 activity. Eplerenone is an effective blocker of nongenomic effects of aldosterone in vascular tissue.

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