Azimilide causes reverse rate-dependent block while reducing both components of delayed-rectifier current in canine ventricular myocytes

Most class III antiarrhythmic drugs reduce the rapidly activating component of delayed-rectifier current (I-Kr) without affecting the slowly activating component (I-Ks). Recently the novel antiarrhythmic agent azimilide (NE-10064) was reported to enhance I-Ks at low (nanomolar) concentrations and to block both I-Kr and I-Ks at higher (micromolar) concentrations. Further to understand the electrophysiologic effects of azimilide, we compared its effects on I-Kr and I-Ks (by using whole cell clamp techniques) and action potentials (microelectrode and perforated-patch techniques) on canine ventricular myocytes. A lower azimilide concentration (50 nM) did not enhance I-Ks In contrast, a therapeutic azimilide concentration (2 mu M) was equieffective in reducing I-Kr (300-ms isochrones) and I-Ks (3-s isochrones) by similar to 40% during depolarizing test pulses, as well as reducing I-Kr (38% decrease) and I-Ks (338 decrease) tail currents on repolarization. Block of I-Ks was independent of voltage at positive test potentials. In action-potential studies, 50 nM azimilide had no effect on the action-potential duration (APD), whereas 2 mu M azimilide delayed repolarization and caused reverse rate-dependent effects on the APD. Whereas the extent of APD prolongation by azimilide was not correlated with the drug-free APD, azimilide preferentially exaggerated the APD-rate relationship of myocytes displaying the steepest APD-rare relationship under drug-free conditions. In conclusion, therapeutic concentrations of azimilide that cause comparable reduction of canine ventricular I-Kr and I-Ks exert reverse rate-dependent effects, which are dependent on the steepness of the APD-rate relationship.