The effects of the specific bradycardic agent,
zatebradine (UL-FS 49), on ventricular arrhythmias occurring during an acute
ischemia were compared to those of
verapamil. Anesthetized rabbits were submitted to a
ligation of the left circumflex coronary artery for 20 min.
Zatebradine (150 and 750 micrograms/kg, i.v.) dose-dependently reduced heart rate, but changed neither the left ventricular pressure nor the (+)dp/dtmax. In comparison,
verapamil (150 and 750 micrograms/kg, i.v.) reduced heart rate, systemic blood pressure, left ventricular pressure and (+)dp/dtmax. The incidence of ventricular
premature beats occurring during acute
ischemia was changed neither by
zatebradine nor by
verapamil.
Ventricular fibrillation, occurring in 36% of the saline-treated rabbits, was reduced to 18% in the presence of 750 micrograms/kg of
zatebradine and 0% with
verapamil (750 micrograms/kg, p < 0.05). The action of
zatebradine on
ischemia-induced
ventricular fibrillation, albeit limited, was completely reversed by atrial pacing to the predrug heart rate. To further investigate the mechanisms involved in the antiarrhythmic potential of both
zatebradine and
verapamil, their electrophysiological actions were compared in canine Purkinje fibers. Both
zatebradine and
verapamil induced a dose-dependent increase in action potential duration (APD) measured at 90% repolarization. The APDs measured during the plateau level (APD30) and at 50% of the repolarization (APD50) were shortened by
verapamil and increased by
zatebradine showing that at the concentrations used,
zatebradine did not exhibit any
calcium antagonistic activity when compared to
verapamil. The results of the present study suggest that the specific bradycardic agent
zatebradine showed a beneficial action mainly because of its anti-ischemic properties. However, the present studies performed in anesthetized rabbits suggest that in this species pure reduction in heart rate is not sufficient to entirely prevent ischemic arrhythmias.