Effects of cardiotoxic doses of adrenergic amines on myocardial cyclic AMP.

The role of beta-adrenergic activation in the cardiotoxicity of adrenergic amines was assessed by measuring rat myocardial cyclic AMP at various times after subcutaneous injection of necrosis-inducing amounts of isoproterenol, phenylephrine or epinephrine in the presence and in the absence of the phosphodiesterase inhibitor aminophylline. The β-adrenergic agonist isoproterenol (5.25 mg/kg) increased myocardial cyclic AMP at 1 h to 147% of control and in the presence of aminophylline (75 mg/kg) to 261% of control as compared to 146% for aminophylline alone. Propranolol (6.25 mg/kg) blocked isoproterenol-induced increases in cyclic AMP. Neither the α-adrenergic agonist phenylephrine (15 mg/kg) nor epinephrine (4 mg/kg), which has both α- and β-adrenergic properties, increased myocardial cyclic AMP above control levels even in the presence of aminophylline. With α-adrenergic blockade by tolazoline (15 mg/kg) or phenoxybenzamine (2 mg/kg), combined administration of epinephrine and aminophylline caused an increase of the myocardial cyclic AMP content to 163% and 173%, respectively, of that of control rats. These results suggest that in the intact rat, cyclic AMP-mediated myocardial stimulation is an important factor in the cardiotoxicity of isoproterenol but not of phenylephrine, while the beta-adrenergic component of epinephrine cardiotoxicity is unmasked only in the presence of α-adrenergic blockade.