Blockade of the pacemaker current by intracellular application of UL-FS 49 and UL-AH 99 in sheep cardiac Purkinje fibers

Abstract

UL-FS 49 (Zatebradine) and its quaternary derivative, UL-AH 99, were injected by iontophoresis in shortened sheep cardiac Purkinje fibres. The i f pacemaker current changes were analyzed using the two-microelectrode voltage-clamp technique. Injection of either drug resulted in a decrease of the maximal diastolic depolarization rate as a consequence of a reduction in i f amplitude, with no changes in the kinetics of this current or in voltage dependence. The i f blockade was proportional to the total charge injected. After drug iontophoresis under conditions where no i f current was activated, an exponential use-dependent decline in i f tail current was observed during the application of a voltage-clamp pulse train activating i f. A slow recovery from blockade, measured after prolonged hyperpolarizations, followed exponential kinetics. Recovery rate and extent of steady state recovery increased with more negative potentials. This suggests that bradycardiac agents interact with the i f channel in cationic form from the inside of the cell.