SUSTAINED DEPOLARIZATION-INDUCED OUTWARD CURRENT IN HUMAN ATRIAL MYOCYTES - EVIDENCE FOR A NOVEL DELAYED RECTIFIER K+ CURRENT SIMILAR TO KV1.5 CLONED CHANNEL CURRENTS

被引:481
作者
WANG, ZG
FERMINI, B
NATTEL, S
机构
[1] MONTREAL HEART INST,DEPT MED,5000 BELANGER ST E,MONTREAL H1T 1C8,QUEBEC,CANADA
[2] UNIV MONTREAL,MONTREAL H3C 3J7,QUEBEC,CANADA
[3] MCGILL UNIV,DEPT PHARMACOL & THERAPEUT,MONTREAL H3A 2T5,QUEBEC,CANADA
关键词
K+ CURRENTS; REPOLARIZATION; ARRHYTHMIAS; CARDIAC; ELECTROCARDIOGRAPHY; ACTION POTENTIAL;
D O I
10.1161/01.RES.73.6.1061
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Depolarization of human atrial myocytes activates a transient outward, current that rapidly inactivates, leaving a sustained outward current after continued depolarization. To evaluate the ionic mechanism underlying this sustained current (I(sus)), we applied whole-cell voltage-clamp techniques to single myocytes isolated from right atrial specimens obtained from patients undergoing coronary bypass surgery. The magnitude of I(sus) was constant for up to 10 seconds at +30 mV and was unaffected by 40 mmol/L tetraethylammonium, 100 nmol/L dendrotoxin, 1 mmol/L Ba2+, 0.1 mumol/L atropine, or removal of Cl- in the superfusate. I(sus) could be distinguished from the 4-aminopyridine (4AP)-sensitive transient outward current (I(tol)) by differences in voltage-dependent inactivation (1000-millisecond prepulse to -20 mV reduced I(tol) by 91.7+/-0.1% [mean+/-SEM], P<.001, versus 9.4+/-0.4% reduction of I(sus)) and 4AP sensitivity (IC50 for block of I(tol), 1.96 mmol/L; for I(sus), 49 mumol/L). I(sus) activation had a voltage threshold near -30 mV, a half-activation voltage of -4.3 mV, and a slope factor of 8.0 mV. I(sus) was not inactivated by 1000-millisecond prepulses but was reduced by 16+/-8% (P<.05) at a holding potential of -20 mV relative to values at a holding potential of -80 mV. I(sus) activated very rapidly, with time constants (tau) at 25-degrees-C ranging from 18.2+/-1.8 to 2.1+/-0.2 milliseconds at -10 to +50 mV, two orders of magnitude faster than previously described kinetics of the rapid component of the delayed rectifier K+ current. At 16-degrees-C, I(sus), activation was greatly slowed (tau at +10 mV, 46.7+/-4.1 milliseconds; tau at 25-degrees-C, 7.1+/-0.8 milliseconds; P<.01), and the envelope of tails test was satisfied. The reversal potential of I(sus), tail currents changed linearly with log [K+]o (slope, 55.3+/-2.9 mV per decade), and the fully activated current-voltage relation showed substantial outward rectification. Selective inhibition of I(sus), with 50 mumol/L 4AP increased human atrial action potential duration by 66+/-11% (P<.01). In conclusion, I(sus) in human atrial myocytes is due to a very rapidly activating delayed rectifier K+ current, which shows limited slow inactivation is insensitive to tetraethylammonium, Ba2+, and dendrotoxin, and is highly sensitive to 4AP. These properties resemble the characteristics of channels encoded by the Kv1.5 group of cardiac cDNAs and may represent a physiologically significant manifestation of such channels in human atrium.
引用
收藏
页码:1061 / 1076
页数:16
相关论文
共 52 条
[1]   CHARACTERIZATION OF 2 DISTINCT DEPOLARIZATION-ACTIVATED K+ CURRENTS IN ISOLATED ADULT-RAT VENTRICULAR MYOCYTES [J].
APKON, M ;
NERBONNE, JM .
JOURNAL OF GENERAL PHYSIOLOGY, 1991, 97 (05) :973-1011
[2]   BACKGROUND POTASSIUM CURRENT ACTIVE DURING THE PLATEAU OF THE ACTION-POTENTIAL IN GUINEA-PIG VENTRICULAR MYOCYTES [J].
BACKX, PH ;
MARBAN, E .
CIRCULATION RESEARCH, 1993, 72 (04) :890-900
[3]  
Bigger JT, 1985, PHARMACOL BASIS THER, P748
[4]   A NOVEL TYPE OF DEPOLARIZATION-ACTIVATED K+ CURRENT IN ISOLATED ADULT-RAT ATRIAL MYOCYTES [J].
BOYLE, WA ;
NERBONNE, JM .
AMERICAN JOURNAL OF PHYSIOLOGY, 1991, 260 (04) :H1236-H1247
[5]   VOLTAGE-CLAMP INVESTIGATIONS OF MEMBRANE CURRENTS UNDERLYING PACE-MAKER ACTIVITY IN RABBIT SINO-ATRIAL NODE [J].
BROWN, H ;
DIFRANCESCO, D .
JOURNAL OF PHYSIOLOGY-LONDON, 1980, 308 (NOV) :331-351
[6]   SIMPLIFIED GENE NOMENCLATURE [J].
CHANDY, KG ;
DOUGLAS, J ;
GUTMAN, GA ;
JAN, L ;
JOHO, R ;
KACZMAREK, L ;
MCKINNON, D ;
NORTH, RA ;
NUMA, S ;
PHILIPSON, L ;
RIBERA, AB ;
RUDY, B ;
SALKOFF, L ;
SWANSON, R ;
STEINER, D ;
TANOUYE, M ;
TEMPEL, BL .
NATURE, 1991, 352 (6330) :26-26
[7]   KINETICS AND MAGNITUDE OF THE TIME-DEPENDENT POTASSIUM CURRENT IN THE RABBIT SINOATRIAL NODE - EFFECT OF EXTERNAL POTASSIUM [J].
DIFRANCESCO, D ;
NOMA, A ;
TRAUTWEIN, W .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1979, 381 (03) :271-279
[8]   SUSTAINED OUTWARD CURRENT OBSERVED AFTER ITO1 INACTIVATION IN RABBIT ATRIAL MYOCYTES IS A NOVEL CL- CURRENT [J].
DUAN, DY ;
FERMINI, B ;
NATTEL, S .
AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 263 (06) :H1967-H1971
[9]   THE TRANSIENT K+ CURRENT IN RAT VENTRICULAR MYOCYTES - EVALUATION OF ITS CA2+ AND NA+ DEPENDENCE [J].
DUKES, ID ;
MORAD, M .
JOURNAL OF PHYSIOLOGY-LONDON, 1991, 435 :395-420
[10]   2 TYPES OF TRANSIENT OUTWARD CURRENTS IN ADULT HUMAN ATRIAL CELLS [J].
ESCANDE, D ;
COULOMBE, A ;
FAIVRE, JF ;
DEROUBAIX, E ;
CORABOEUF, E .
AMERICAN JOURNAL OF PHYSIOLOGY, 1987, 252 (01) :H142-H148