Frequency-dependent Cardiac Electrophysiologic Effects of Tedisamil: Comparison With Quinidine and Sotalol

Abstract

Background: Tedisamil is a potent bradycardic/antiischemic drug known to lengthen car diac repolarization by blocking various potassium channels. Recent in vivo experiments revealed that it is an antiarrhythmic agent. It was therefore of interest to compare the cellu lar electrophysiologic effects of tedisamil with those of quinidine and sotalol in isolated car diac preparations.

Methods and Results: The conventional microelectrode technique was applied in isolated dog cardiac Purkinje and ventricular muscle fibers and in rabbit left atrial muscle. Tedisamil (1 μM) and sotalol (30 μM) lengthened, while quinidine (10 μM) shortened action potential duration in dog Purkinje fibers. The phase 1 repolarization was delayed by tedisamil and quinidine and not changed by sotalol. In dog ventricular muscle and in rabbit atrial muscle, all three drugs studied lengthened repolarization. In dog Purkinje fiber, tedisamil and sotalol lengthened action potential duration more at slow than at high stimulation frequency (reverse use-dependence). In dog ventricular muscle fibers, the effect of the drugs was not clearly fre quency dependent. In rabbit atrial muscle fibers, the quinidine-evoked repolariration length ening was most pronounced at intermediate cycle lengths (500-1000 ms). Tedisamil and quinidine but not sotalol depressed the maximal rate of depolarization (V_max), which depended on the stimulation frequency (use-dependence). The nature of the use-dependent V_max block differed between quinidine and tedisamil. Quinidine decreased V_max at a relatively wide range of stimulation frequencies while tedisamil decreased V_max largely at high rate of stimulation. Tedisamil and quinidine prevented or decreased the pinacidil-evoked action potential shortening in dog ventricular muscle, suggesting block of the ATP-dependent potas sium channels (I_KATP), while with sotalol such effect was not observed.

Conclusions: Although tedisamil, quinidine. and sotalol are known to lengthen the QT inter val, their cellular electrophysiologic effects substantially differ. Tedisamil lengthens repolar ization and prevents pinacidil-evoked action potential duration shortening, suggesting I_K(ATP) blockade. Its effect on the V_max is limited mostly to fast heart rate. These electrophysiologic effects of tedisamil resemble those of chronic amiodarone treatment.