Effect of RP58866 on Ventricular Arrhythmias in Rat, Rabbit, and Primate

Background. The effectiveness of blockade of the inwardly rectifying K ' current (IK1) in prevention of arrhythmias is unknown. We have examined the antiarrhythmic potential of a new selective IKI blocker, RP58866, in rat, rabbit, and primate (marmoset) isolated hearts in the settings of acute ischemia and reperfusion. Methods and Results. In concentration-response studies (n=12 per group), the drug reduced ischemia-induced ventricular fibrillation (VF) in rat from control incidence of 100 to 50%o, 17 % (p<0.05), and 0%7 (p<0.05) at 1, 3, and 10 gmol/L, respectively. RP58866 produced significant bradycardia at the 3- and 10-,gmol/L concentrations and significant QT interval widening at all three concentrations (p<0.05). When rat hearts (n=12 per group) were paced (5 Hz) via the left atrium to prevent bradycardia, the antiarrhythmic effects of 10-,umol/L RP58866 were unmodified (ischemia-induced VF incidence was reduced by drug from 83 % in control hearts to 8%; p<0.05). Similarly, pacing did not prevent the drug's QT-widening activity at 90 % repolarization (QT90 was 64±3 msec in control hearts versus 128±17 msec in the presence of 10,umol/L of drug after 10 minutes of ischemia; p<O.05). These values are similar to equivalent values in unpaced hearts (65±3 msec in control hearts versus 159±15 msec with 10,umol/L of drug; p<O.05). In separate groups of rat hearts (n=10 per group) subjected to 10 minutes of ischemia