Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon 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 epsilon PKC (epsilonPKC) inhibition but neither alphaPKC nor scrambled epsilonPKC; addition of epsilonPKC activator peptide mimicked the rapid aldosterone effect. In rabbits chronically infused with aldosterone, the lowered pump current in cardiomyocytes was acutely (< or =15 min) restored by epsilonPKC inhibition. These studies show that rapid effects of aldosterone on Na+-K+ pump activity are nongenomic and specifically epsilonPKC mediated; in addition, such effects may be prolonged (7 d) and long-lived ( approximately 4 h isolated cardiomyocyte preparation time). The rapid, prolonged, long-lived effects can be rapidly (< or =15 min) reversed by epsilonPKC blockade, suggesting a hitherto unrecognized complexity of aldosterone action in the heart and perhaps by extension other tissues.
Mihailidou
Anastasia S
AS
Department of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, New South Wales 2065, Australia. amihaili@med.usyd.edu.au
Mardini
Mahidi
M
Funder
John W
JW
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D032342:Muscle Cells / Q000502:physiology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D011817:Rabbits; D028021:Sodium-Potassium-Chloride Symporters / Q000187:drug effects / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000502:physiology; D016276:Ventricular Function
D004791:Enzyme Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D000450:Aldosterone; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D000254:Sodium-Potassium-Exchanging ATPase