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Ventricular fibrillation threshold and myocardial cyclic AMP production in rats sensitive or resistant to isoproterenol.

Beta-Adrenoceptor agonists, such as isoproterenol, produce ventricular fibrillation and myocardial necrosis in rats. After the initial insult, a resistance develops to the lesion-inducing effects of subsequent doses of the drug. Cyclic AMP has been considered to play a major role in beta-adrenergic amine-induced myocardial necrosis as well as in the genesis of ventricular fibrillation. In the present studies, we investigated the ventricular fibrillation threshold and the responsiveness of myocardium to cAMP formation in isoproterenol-sensitive and resistant rats. Myocardial necrosis was induced in male Sprague-Dawley rats by subcutaneous injection of isoproterenol at 50 micrograms/kg for 2 consecutive days to make them resistant to subsequent challenges. Control rats received saline. Both groups were challenged 10 days later with graded doses of isoproterenol and ECGs were recorded. In another experiment, hearts from rats similarly treated were used for histopathology and cAMP determinations. The incidence of ventricular fibrillation and death was significantly lower in resistant rats compared with isoproterenol-sensitive rats. All rats pretreated with isoproterenol showed healed myocardial necrosis. The basal myocardial cAMP levels and the levels after in vitro isoproterenol stimulation were not significantly different between isoproterenol- and saline-pretreated rats. Moreover, no significant differences in the responsiveness of myocardium to cAMP formation were noted between the more sensitive apical and less sensitive ventricular regions in resistant or sensitive rats. These data indicate that the altered myocardial sensitivity or the mechanism for the increased ventricular fibrillation threshold in isoproterenol resistance appears to involve factors other than cAMP.