title: Arrhythmogenic action of alpha 1-adrenoceptor stimulation in normoxic rat ventricular myocardium: influence of nisoldipine, reduced extracellular Ca2+ and ryanodine.
abstract: This study examines the arrhythmogenic action of alpha 1 and alpha 2-adrenoceptor stimulation in the isolated perfused rat heart. The alpha 1-agonist methoxamine in the presence of the beta 1-antagonist atenolol 10(-6) M decreased the ventricular fibrillation threshold in the normoxic rat ventricular myocardium: VFT values (mA): Control 11.2 +/- 0.5; methoxamine 10(-6) M 4.9 +/- 0.9 (P less than 0.01 vs control); methoxamine 10(-5) M 3.5 +/- 0.5 (P less than 0.01 vs control). The alpha 1-antagonist prazosin 10(-8) M prevented the methoxamine-induced fall in ventricular fibrillation threshold. The alpha 2-agonist BHT 933 (azepexole) in the presence of atenolol 10(-6) M produced no alteration in the ventricular fibrillation threshold. Methoxamine 10(-6) M to 10(-5) M had a positive inotropic effect with increased left ventricular pressure development, myocardial oxygen consumption and QT-interval; however, tissue levels of cyclic AMP remained unchanged. Methoxamine 10(-6) M did not alter heart rate, coronary flow rate or deplete tissue levels of adenosine triphosphate, phosphocreatine or glycogen. The enhanced vulnerability to ventricular fibrillation induced by methoxamine could be demonstrated only at supraphysiological extracellular calcium concentrations (2.5 mM) but not at physiological calcium concentrations (1.25 mM). The arrhythmogenic and inotropic effect of methoxamine 10(-6) M was prevented by inhibition of transsarcolemmal Ca2+ ion influx by nisoldipine 10(-8) M or by inhibition of release of Ca2+ from sarcoplasmic reticulum by ryanodine 10(-9) M to 10(-8) M. Thus in isolated normoxic rat heart preparations, activity of the alpha 1-receptor appears to mediate ventricular arrhythmogenesis but only in the setting of myocardial calcium overload. The arrhythmogenic effect of alpha 1-stimulation may be due to increased transsarcolemmal calcium influx and enhanced release of calcium from the sarcoplasmic reticulum; increased myocardial oxygen consumption secondary to greater left ventricular pressure development may contribute in part.
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001381:Azepines / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015737:Nisoldipine; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012433:Ryanodine / Q000494:pharmacology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000470:Alkaloids; D001381:Azepines; D002121:Calcium Channel Blockers; D012433:Ryanodine; D015737:Nisoldipine; C015603:azepexole; D008729:Methoxamine; D009543:Nifedipine; D002118:Calcium; D011224:Prazosin