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Protein Kinase C
Department of Cardiology (A.S.M., M.M.), Royal North Shore Hospital, Sydney 2065, Australia; Faculty of Medicine, University of Sydney 2006 (A.S.M., M.M.); Department of Cardiology (M.M.), Westmead Hospital, Sydney 2145, Australia; and Prince Henry’s Institute of Medical Research (J.W.F.), Clayton, Victoria 3168, Australia
Address all correspondence and requests for reprints to: Dr. Anastasia Susie Mihailidou, Department of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, New South Wales, Australia 2065. E-mail: amihaili{at}med.usyd.edu.au.
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.
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