Selective Class III Antiarrhythmic Properties of a Novel Agent, UK‐66,914, During Chronic Myocardial Infarction

Abstract

Antiarrhythmic Properties of UK‐ 66,914. UK‐66,914 is a potent Class III antiarrhythmic agent that has no effect on conduction velocity in normal tissue in vitro. The present study was performed to evaluate the influence of UK‐66,914 on conduction velocity in vivo in canine hearts with a previous myocardial infarction. Detailed three‐dimensional mapping of the heart in vivo was obtained using simultaneous recordings from 232 transmural sites. In dogs with a chronic anterior myocardial infarction, UK‐66,914 (50 μg/kg) did not alter conduction velocity in regions exhibiting normal conduction (gt; 50 cm/sec) or regions with slowed conduction (< 50 cm/sec) despite an 11%‐15% increase in the ventricular effective refractory period. UK‐66,914 prevented the induction of ventricular tachycardias by programmed electrical stimulation due to lengthening of the effective refractory period with no direct or indirect effects on conduction velocity in dogs with chronic infarcts of 1‐year duration. Because the endocardial border zone surrounding the infarct was critical to the development of the reentrant pathway in vivo, studies were performed in tissue from this region in vitro utilizing a high‐resolution, 224 bipolar grid recording array. The effects of UK‐66,914, d‐sotalol, and procainamide on conduction velocity were compared in this region at concentrations that elicited a comparable increase in the effective refractory period of 40 msec. UK‐66,914 and d‐sotalol did not alter conduction velocity in regions with conduction velocities > 30 cm/sec, 15‐30 cm/sec, or < 15 cm/sec, whereas procainamide significantly decreased conduction velocity at all three levels. Evaluation of the hemodynamic profile of UK‐66,914 revealed no negative ionotropic effects in conscious dogs even at doses twentyfold those required to elicit increases in the effective refractory period. Therefore, UK‐66,914 is a potent and specific Class III antiarrhythmic agent, which does not alter conduction velocity in hearts with a previous myocardial infarction and exerts no negative inotropic effects.