Voltage-dependent blockade in Na+-dependent action potentials after β1- and H2-receptor stimulation in mammalian ventricular myocardium

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Abstract
In isolated papillary muscles of guinea pigs, the influence of isoproterenol, histamine, theophylline, and phenylephrine on the maximal rate of rise (.ovrhdot.Vmax) of Na+-dependent action potentials and on isometric contractile force was studied under rested state conditions. Isoproterenol (1 .times. 10-7 mol/L), histamine (2 .times. 10-5 mol/L), and theophylline (2 .times. 10-3 mol/L) shifted the voltage dependence of .ovrhdot.Vmax into the hyperpolarizing direction and, consequently, led to a voltage-dependent .ovrhdot.Vmax blockade. The .alpha.-adrenoceptor agonist phenylephrine, on the other hand, proved to be ineffective in depressing .ovrhdot.Vmax. The .beta.-receptor blocker pindolol (4 .times. 10-6 mol/L) or the H2-receptor blocker cimetidine (4 .times. 10-5 mol/L) abolished the inhibitory effects of isoproterenol and histamine, respectively, and caused .ovrhdot.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 .ovrhdot.Vmax compared with its positive inotropic action. The IC50 value of the former effect amounted to approximately 5 .times. 10-6 mol/L, but the EC50 value of the latter effect was 4 .times. 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.

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