Loss of adenosine-induced negative inotropic effect in hyperexcited rabbit hearts: relationship to PKC.
Adenosine produced a negative inotropic effect in hearts isolated from calm rabbits but not from those exhibiting alarm behavior during handling. This study was conducted to determine whether protein kinase C (PKC) activation is responsible for the loss of adenosine-induced negative inotropism in the hearts of hyperexcited rabbits. Adenosine (10 microM) decreased myocardial contractility (dP/dtmax) in the hearts of calm, but not hyperexcited, rabbits but decreased heart rate (HR) and coronary perfusion pressure (PP) in the hearts of both calm and hyperexcited animals. During infusion of calphostin C (200 nM), a PKC inhibitor, adenosine also decreased dP/dtmax in the hearts of hyperexcited rabbits. Calphostin C did not alter the actions of adenosine in the hearts of calm rabbits. Agents that stimulate PKC directly [phorbol 12,13-dibutyrate (PDBu), 1 nM] or indirectly [norepinephrine (NE), 3 nM; angiotensin II (ANG II), 5 nM] abolished the adenosine-induced decrease in dP/dtmax but not HR or PP in the hearts of calm rabbits. During calphostin C, infusion of PDBu, NE, and ANG II failed to prevent the adenosine-induced decrease in dP/dtmax. These data suggest that the lack of a negative inotropic effect of adenosine in hyperexcited rabbits is due to an increase in PKC activity.
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Department of Pharmacology, College of Medicine, University of Tennessee, Memphis 38163.
Slavik
K J
KJ
Malik
K U
KU
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004789:Enzyme Activation; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology*; D009281:Naphthalenes; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D010646:Phentolamine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D001713:Biphenyl Compounds; D007093:Imidazoles; D009281:Naphthalenes; D011083:Polycyclic Compounds; D013777:Tetrazoles; D000804:Angiotensin II; D015240:Phorbol 12,13-Dibutyrate; D011433:Propranolol; D011493:Protein Kinase C; C058819:calphostin C; D019808:Losartan; D000241:Adenosine; D000109:Acetylcholine; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine; D010646:Phentolamine