EFFECTS OF ZATEBRADINE ON OUABAIN-INDUCED, 2-STAGE CORONARY LIGATION-INDUCED AND EPINEPHRINE-INDUCED VENTRICULAR TACHYARRHYTHMIAS

To determine whether a hyperpolarization-activated current (I-f) parti cipates in ventricular tachyarrhythmias, we investigated the effects o f zatebradine, an I-f inhibitor, on the ventricular tachyarrhythmias i nduced by ouabain, two-stage coronary ligation and epinephrine infusio n in the dog heart. We determined atrial rate, ectopic ventricular rat e, total heart I-ate and arrhythmic ratio (the number of ectopic ventr icular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ect opic ventricular rate and atrial rate of the ouabain-induced ventricul ar tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by zatebradine of the ventricular arrhythmias needed larger doses tha n the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricul ar arrhythmias induced by two-stage coronary ligation 24 h after the l igation in conscious dogs. Although neither the ectopic ventricular ra te nor the arrhythmic ratio of the epinephrine-induced ventricular arr hythmias was affected by zatebradine, after treatment with zatebradine , the arrhythmias elicited by epinephrine developed more slowly. Toget her with the previously reported spectra of the effects of the antiarr hythmic agents in three ventricular tachyarrhythmia models, our result s suggest that zatebradine may improve automaticity-related ventricula r tachyarrhythmias due to I-f inhibition or to other undetermined mech anisms in the heart.