USE-DEPENDENT BLOCK OF THE PACEMAKER CURRENT I(F) IN RABBIT SINOATRIAL NODE CELLS BY ZATEBRADINE (UL-FS-49) - ON THE MODE OF ACTION OF SINUS NODE INHIBITORS

Background. Zatebradine (UL-FS 49) is a drug with a specific bradycard iac electrophysiological profile. It reduces heart rate by lengthening the duration of diastolic depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified. Methods an d Results. We used the whole-cell patch-clamp technique to study the e ffects of zatebradine on ionic currents underlying diastolic depolariz ation of isolated rabbit SA node cells. Low concentrations of zatebrad ine simultaneously reduced diastolic depolarization rate and the pacem aker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically rel evant concentrations of the drug have little effect on the L-type calc ium current or delayed rectifier potassium current. Conclusions. This use-dependent block of the I(f) channel can account for most of the ph armacological characteristics of zatebradine and is probably the mecha nism of heart rate reduction caused by this agent. Thus, the sinus nod e inhibitor zatebradine belongs to a new class of ''I(f) blockers'' wi th possible advantages over currently available drugs for the treatmen t of ischemic heart disease.