Inhibition of Vmax of the action potential by propafenone and its voltage-, time- and pH-dependence in mammalian ventricular myocardium.

Abstract

In microelectrode experiments on isolated papillary muscles of guinea-pigs, the effect of propafenone (1×10−5 mol/l–1×10−4 mol/l) on the fast Na+ action potential was analyzed. Propafenone caused, without changing the resting potential, a concentration dependent decrease of $$\dot V_{\max } $$ . At continuous stimulation with a rate of 12/min, complete inhibition of $$\dot V_{\max } $$ appeared in response to 1×10−4 mol/l. Transformation of the concentration-response curve into the Hill form revealed a Hill coefficient of 1.8. Some minor changes of the action potential configuration occurred consisting of a plateau shift to less positive potentials and of an abbreviation of action potential duration. Propafenone did not alter the linear dependence of $$\dot V_{\max } $$ on the logarithm of external Na+ concentration. Propafenone shifted the curve relating $$\dot V_{\max } $$ to membrane potential (h ∞-curve) to more negative potentials suggesting an interference with the inactivation process of the fast Na+ system. This effect developed on the quiescent, non-stimulated preparation and leads to the occurrence of a resting-state block being, consequently, potential dependent. Repetitive stimulation enhanced the propafenone-induced inhibition indicating a use-dependent block. During a train of 5–7 (at 12/min) or 15–20 (at 120/min) action potentials, a continuous decline of $$\dot V_{\max } $$ occurred until a new steady-state was attained. The interstimulus interval determined strength and kinetics of development (τdevelopment) of the use-dependent block. It was 22% and 8.4s, respectively at 5000 ms, but 70% and 1.8 s, respectively, at 500 ms. A slight intensification could also be induced by a decrease of membrane potential whilst pH or temperature changes remained ineffective. After cessation of continuous stimulation, the use-dependent block disappeared with a time constant of 15.5 s. Neither an increase of pH from 7.4 to 8.4 nor a decrease to 6.4 had any influence on the action of propafenone (pK a=9.0). Resting-state and usedependent block were of an identical amount regardless of the pH in the medium.