title: Activation of PKC decreases myocardial O2 consumption and increases contractile efficiency in rats.
abstract: The effect of protein kinase C (PKC) activation on cardiac mechanoenergetics is not fully understood. To address this issue, we determined the effects of the PKC activator phorbol 12-myristate 13-acetate (PMA) on isolated rat hearts. Hearts were exposed to PMA with or without pretreatment with the PKC inhibitor chelerythrine. Contractile efficiency was assessed as the reciprocal of the slope of the linear myocardial O2 consumption (VO2) pressure-volume area (PVA) relation. PMA decreased contractility (Emax; -30 +/- 8%; P < 0.05) and increased coronary perfusion pressure (+58 +/- 11%; P < 0.01) without altering left ventricular end-diastolic pressure. Concomitantly, PMA decreased PVA-independent VO2 [nonmechanical energy expenditure for excitation-contraction (E-C) coupling and basal metabolism] by 28 +/- 8% (P < 0.05) and markedly increased contractile efficiency (+41 +/- 8%; P < 0.05) in a manner independent of the coronary vascular resistance. Basal metabolism was not affected by PMA. Chelerythrine abolished the PMA-induced vasoconstriction, negative inotropy, decreased PVA-independent VO2, and increased contractile efficiency. We conclude that PKC-mediated phosphorylation of regulatory proteins reduces VO2 via effects on both the contractile machinery and the E-C coupling.
authors.affiliation: Cardiology Unit, Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05401, USA.
authors.forename: T
authors.initials: T
authors.lastname: Noguchi
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: S P
authors.initials: SP
authors.lastname: Bell
authors.forename: L
authors.initials: L
authors.lastname: Nyland
authors.forename: M M
authors.initials: MM
authors.lastname: LeWinter
mesh_terms: D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002273:Carcinogens / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000470:Alkaloids; D053119:Benzophenanthridines; D002273:Carcinogens; D004791:Enzyme Inhibitors; D010617:Phenanthridines; C016299:chelerythrine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate