Rapid, Nongenomic Effects of Aldosterone in the Heart Mediated by Protein Kinase C

Aldosterone elevates Na /K /2Cl cotransporter activity in rabbit cardiomyocytes within 15 min, an effect blocked by K-canrenoate and thus putatively mineralocorticoid receptor mediated. Increased cotransporter activity raises intracellular [Na ] sufficient to produce a secondary increase in Na -K pump activity; when this increase in intracellular [Na ] is prevented, a rapid effect of aldosterone to lower pump activity is seen. Addition of transcription inhibitor actinomycin D did not change basal or aldosterone-induced lowered pump activity, indicating a direct, nongenomic action of aldosterone. We examined a possible role for protein kinase C (PKC) in the rapid nongenomic effects of aldosterone. Single ventricular myocytes and pipette solutions containing 10 mM intracellular [Na ] were used in patch clamp studies to measure Na -K pump activity. Aldosterone lowered pump current, an effect abolished by PKC ( PKC) inhibition but neither PKC nor scrambled PKC; addition of PKC activator peptide mimicked the rapid aldosterone effect. In rabbits chronically infused with aldosterone, the lowered pump current in cardiomyocytes was acutely (<15 min) restored by PKC inhibition. These studies show that rapid effects of aldosterone on Na -K pump activity are nongenomic and specifically PKC mediated; in addition, such effects may be prolonged (7 d) and long-lived ( 4 h isolated cardiomyocyte preparation time). The rapid, prolonged, long-lived effects can be rapidly (<15 min) reversed by PKC blockade, suggesting a hitherto unrecognized complexity of aldosterone action in the heart and perhaps by extension other tissues. (Endocrinology 145: 773–780, 2004)