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

被引:200
作者
Bosch, RF
Gaspo, R
Busch, AE
Lang, HJ
Li, GR
Nattel, S
机构
[1] Montreal Heart Inst, Dept Med, Montreal, PQ H1T 1C8, Canada
[2] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada
[3] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada
[4] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3A 2T5, Canada
[5] Univ Tubingen, Inst Physiol, Tubingen, Germany
[6] Hoechst AG, D-6230 Frankfurt, Germany
基金
英国医学研究理事会;
关键词
potassium channels; action potential; biophysics; cardiac arrhythmias; antiarrhythmic drugs;
D O I
10.1016/S0008-6363(98)00021-2
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:441 / 450
页数:10
相关论文
共 53 条
[1]  
[Anonymous], 1989, NEW ENGL J MED, V321, P406
[2]   CLINICAL RELEVANCE OF CARDIAC-ARRHYTHMIAS GENERATED BY AFTERDEPOLARIZATIONS - ROLE OF M-CELLS IN THE GENERATION OF U WAVES, TRIGGERED ACTIVITY AND TORSADE-DE-POINTES [J].
ANTZELEVITCH, C ;
SICOURI, S .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 1994, 23 (01) :259-277
[3]  
ANTZELEVITCH C, 1995, CARDIAC ELECTROPHYSI, P228
[4]   CELLULAR ELECTROPHYSIOLOGICAL EFFECTS OF THE CLASS-III ANTIARRHYTHMIC AGENTS SEMATILIDE AND CLOFILIUM ON RABBIT ATRIAL TISSUES [J].
ARGENTIERI, TM ;
CARROLL, MS ;
SULLIVAN, ME .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1991, 18 (01) :167-174
[5]   SUPPRESSION OF TIME-DEPENDENT OUTWARD CURRENT IN GUINEA-PIG VENTRICULAR MYOCYTES - ACTIONS OF QUINIDINE AND AMIODARONE [J].
BALSER, JR ;
BENNETT, PB ;
HONDEGHEM, LM ;
RODEN, DM .
CIRCULATION RESEARCH, 1991, 69 (02) :519-529
[6]  
BOSCH RF, 1996, CIRCULATION S1, V94, P161
[7]  
BOSCH RF, 1997, UNPUB CIRC RES
[8]  
BUSCH AE, 1996, EUR J PHYSL, V432, P1094
[9]   QTU-PROLONGATION AND TORSADES-DE-POINTES INDUCED BY PUTATIVE CLASS-III ANTIARRHYTHMIC AGENTS IN THE RABBIT - ETIOLOGY AND INTERVENTIONS [J].
CARLSSON, L ;
ALMGREN, O ;
DUKER, G .
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1990, 16 (02) :276-285