Rapid, Nongenomic Effects of Aldosterone in the Heart Mediated by ε 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 ε PKC (εPKC) inhibition but neither αPKC nor scrambled εPKC; addition of εPKC 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 εPKC inhibition. These studies show that rapid effects of aldosterone on Na⁺-K⁺ pump activity are nongenomic and specifically εPKC 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 εPKC blockade, suggesting a hitherto unrecognized complexity of aldosterone action in the heart and perhaps by extension other tissues.