Role of Ca(2+)-independent PKC in alpha 1-adrenoceptor-mediated inotropic responses of neonatal rat hearts.
We investigated the role of protein kinase C (PKC) in alpha 1-adrenoceptor (alpha 1-AR)-mediated positive inotropic responses of neonatal rat myocardium. Bisindolylmaleimide (BIM), an inhibitor of all PKC isoforms, reduced the positive inotropic responses to phenylephrine and methoxamine but not to isoproterenol. The positive inotropic effect of phenylephrine was not attenuated by Gö-6976, a selective inhibitor of Ca(2+)-dependent isoforms; it was potentiated by the 1,2-diacylglycerol kinase inhibitor R-59949. Phorbol 12,13-dibutyrate, an activator of both Ca(2+)-dependent and-independent PKC isoforms, as well as thymeleatoxin, a selective activator of Ca(2+)-dependent PKC isoforms, inhibited myocardial contractions, which were prevented by BIM and Gö-6976. BIM inhibited the phenylephrine-induced increase in particulate PKC activity but not the increase in phosphatidylinositide turnover. Phenylephrine induced translocation of only Ca(2+)-independent PKC-epsilon and -delta. These results suggest that activation of Ca(2+)-independent PKC isoforms by alpha 1-AR agonists plays a key role in alpha 1-AR-mediated positive inotropic effect on neonatal myocardium.
Deng
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XF
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Mulay
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Varma
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D019852:Diacylglycerol Kinase; D004558:Electric Stimulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008729:Methoxamine / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D052999:Quinazolinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007295:Inositol Phosphates; D007527:Isoenzymes; D008301:Maleimides; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; D018340:Receptors, Adrenergic, alpha-1; C058544:R 59949; C081021:Go 6976; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; D017853:Phosphotransferases (Alcohol Group Acceptor); D019852:Diacylglycerol Kinase; D011493:Protein Kinase C; D008729:Methoxamine; D007545:Isoproterenol; C088060:bisindolylmaleimide; D002118:Calcium