Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes

Objectives: The slow component of the delayed rectifier K+ current (I,) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by minK and not KERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes. Methods: Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36 degrees C. Results: Delayed rectifier current (I-K) elicited by pulses to + 60 mV from a holding potential of - 50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9 +/- 0.8%; 50% inhibitory concentration, EC50, 1.02 mu M), but I-K during pulses to -10 mV was unaffected (3.9 +/- 8.4% inhibition at 50 mu M) Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive I-K correspond to those of I-Kr and I-Ks respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 mu M, less than one twentieth the potency for I, inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies. Conclusions: 293B is a selective I,, blocker, and the frequency dependence of APD prolongation caused by this I,, blocker is different from that caused by I,, blockade: 293B may be an interesting tool to study the physiologic role of I,, and the antiarrhythmic potential of I,, blockade. (C) 1998 Elsevier Science B.V. All rights reserved.