Voltage-dependent blockade in Na+-dependent action potentials after β1- 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 [Formula: see text] of Na+-dependent action potentials and on isometric contractile force was studied under rested state conditions. Isoproterenol (1 × 10−7 mol/L), histamine (2 × 10−5 mol/L), and theophylline (2 × 10−3 mol/L) shifted the voltage dependence of [Formula: see text] into the hyperpolarizing direction and, consequently, led to a voltage-dependent [Formula: see text] blockade. The α-adrenoceptor agonist phenylephrine, on the other hand, proved to be ineffective in depressing [Formula: see text]. The β-receptor blocker pindolol (4 × 10−6 mol/L) or the H2-receptor blocker cimetidine (4 × 10−5 mol/L) abolished the inhibitory effects of isoproterenol and histamine, respectively, and caused [Formula: see text] 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 [Formula: see text] compared with its positive inotropic action. The IC50 value of the former effect amounted to approximately 5 × 10−6 mol/L, but the EC50 value of the latter effect was 4 × 10−8 mol/L. It is, therefore, concluded that, in physiologically relevant concentrations, β-adrenergic agonists are unlikely to significantly modulate Na+-dependent excitability even in partially depolarized myocardium.