Voltage-dependent Vmax blockade in Na+-dependent action potentials after beta 1- and H2-receptor stimulation in mammalian ventricular myocardium.

Abstract

In isolated papillary muscles of guinea pigs, the influence of isoproterenol, histamine, theophylline, and phenylephrine on the maximal rate of rise (Vmax) of Na+-dependent action potentials and on isometric contractile force was studied under rested state conditions. Isoproterenol (1 x 10(-7) mol/L), histamine (2 x 10(-5) mol/L), and theophylline (2 x 10(-3) mol/L) shifted the voltage dependence of Vmax into the hyperpolarizing direction and, consequently, led to a voltage-dependent Vmax blockade. The alpha-adrenoceptor agonist phenylephrine, on the other hand, proved to be ineffective in depressing Vmax. The beta-receptor blocker pindolol (4 x 10(-6) mol/L) or the H2-receptor blocker cimetidine (4 x 10(-5) mol/L) abolished the inhibitory effects of isoproterenol and histamine, respectively, and caused Vmax to return to the initial control value. A concentration-response relationship analysis at -65 mV revealed that isoproterenol exerted only a weak inhibitory effect on Vmax compared with its positive inotropic action. The IC50 value of the former effect amounted to approximately 5 x 10(-6) mol/L, but the EC50 value of the latter effect was 4 x 10(-8) mol/L. It is, therefore, concluded that, in physiologically relevant concentrations, beta-adrenergic agonists are unlikely to significantly modulate Na+-dependent excitability even in partially depolarized myocardium.