Electrophysiologic and Antiarrhythmic Effects of the New Class III Antiarrhythmic Drug KCB-328

Background: The electrophysiologic and antiarrhythmic effects of a new class III antiar-rhythmic drug (KCB-328), a delayed rectifier potassium current (IKr) blocker with minimal reverse use-dependent effect on atrial repolarization, were evaluated in the canine night atri-al crush-injury model of atrial flutter (AFL). Methods: Ten anesthetized, open-chest dogs, were studied after right atrial crush-injury. Atrial effective refractory period (ERP), conduction velocity (CV), wavelength, and disper-sion of refractoriness were determined during programmed stimulation (S1S2 at SISI = 200, 300, 400, and 500 msec) at four sites via a mapping plaque sutured on the right atrial free wall. Right and left ventricular ERP were similarly measured at single sites. Electro-physiological parameters were determined at baseline and following sequential cumulative doses of KCB-328 (10, 30, 100. and 300,ug/kg). Results: Sustained AFL was inducible in 7/10 dogs by rapid pacing following baseline elec-trophysiologic measurements. KCB-328 significantly prolonged sinus cycle length, but had no effect on PR interval, and prolonged QTc only at the highest dose level. KCB-328 signif-icantly prolonged atrial ERP and wavelength and ventricular ERP, and significantly reduce