Electrophysiologic effects of nibentan (HE-11) on canine cardiac tissue

We studied the effects of nibentan on transmembrane action potentials of canine Purkinje fibers (PF), ventricular epicardial and endocardial tissues and atrial tissue. Nibentan (1 x 10(-8) to 5 x 10(-6) M) had no effects on maximum diastolic potential of all tissues and produced a modest concentration- and use-dependent decrease in V(max). However, a remarkable tissue specificity was observed in its effects on action potential duration (APD). In PF, the concentration-dependent effect was biphasic: maximum APD prolongation was attained at 10(-7) M, and a decrease in APD was seen at higher concentrations. In contrast, in ventricular tissue, nibentan prolonged APD monotonically to a steady state at 10(-6) M. In atrial tissue, a monotonic, concentration-dependent increase in APD was observed through the highest concentration. The ability of nibentan to prolong PF APD significantly diminished as the cycle length shortened (from 2000 to 300 ms), whereas in ventricular and atrial tissues, it showed no reverse use-dependence. In the physiological range of cycle length, nibentan did not enhance the spatial inhomogeneity of repolarization. In PF, it prolonged APD, slightly inhibited V(max) of Ca++-induced action potentials and completely eliminated the effects of isoproterenol on normal automaticity. We conclude that 1) nibentan is an antiarrhythmic with a profound ability to prolong repolarization while decreasing heterogeneity of repolarization and 2) the extent of nibentan's APD prolongation effect is significantly different in different cardiac tissues.