Pirmenol, a new antiarrhythmic drug with potassium- and sodium-channel blocking activity; a voltage-clamp study in rabbit Purkinje fibres

Abstract

The target of this study was to characterize the effect of pirmenol hydrochloride on the electrophysiological properties of cardiac cells. Action potential studies were carried out using the standard microelectrode technique in isolated rabbit Purkinje fibres. Information about the effect of pirmenol on the fast sodium current was obtained by Vmax-measurement. Furthermore the delayed rectifying current ix was studied by the two microelectrode voltage clamp technique. In concentrations of 0.5-5 mumol/l pirmenol caused a marked prolongation of the action potential duration in isolated rabbit Purkinje fibres. Measurements of the delayed rectifying current ix displayed a strong depression with a KD-value of 1 mumol/l pirmenol. The steady-state current voltage relation showed that pirmenol also caused a reduction of the steady-state sodium window current and/or of the slowly decaying components of the sodium current. In concentrations of greater than or equal to 10 mumol/l pirmenol the action potential duration was diminished again and Vmax was depressed in a use-dependent manner. Furthermore pirmenol caused a depression and a negative shift of the Vmax/Em-relation. Pirmenol blocked sodium channels which recovered from block with a time constant of 6.7 s at a holding potential of -105 mV. Similar to quinidine and sotalol the prolongation of the action potential duration under pirmenol is essentially caused by a diminution of the delayed rectifying current ix. The depression of Vmax is mainly independent from the action potential duration indicating the dominance of an open channel block. Pirmenol is a new drug with class Ia antiarrhythmic action.