USE-DEPENDENT BLOCK AND USE-DEPENDENT UNBLOCK OF THE DELAYED RECTIFIER K+ CURRENT BY ALMOKALANT IN RABBIT VENTRICULAR MYOCYTES

被引:129
作者
CARMELIET, E
机构
[1] Laboratory of Physiology, University of Leuven, Campus Gasthuisberg, Leuven
[2] Laboratory of Physiology, University of Leuven, Campus Gasthuisberg, 3000 Leuven
关键词
DELAYED K+ CURRENT; BLOCK; USE DEPENDENCE; CARDIAC CELLS; ANTIARRHYTHMIC DRUGS; PROLONGATION OF ACTION POTENTIAL; CLASS-III ACTIVITY;
D O I
10.1161/01.RES.73.5.857
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
A voltage-clamp analysis of the effect of almokalant on the delayed rectifier K+ current (I(K)) was made in rabbit ventricular myocytes. The two-suction pipette method was used, and appropriate voltage-clamp protocols were used to study more specifically use dependence, block development, and recovery from block. Almokalant interacted with the I(K) in two ways: it shifted the activation curve in the hyperpolarizing direction (stimulatory effect) and blocked the open I(K) channel in a use-dependent way (inhibitory effect). For 2-second voltage clamps to +20 mV, half-maximum block was obtained at 5 x 10(-8) mol/L, with a Hill coefficient of 1.76. Use-dependent block was related to an open-channel block that occurred at 0 mV with a time constant of 1.07 second and a rather slow recovery from block: at -50 mV, recovery time constant was almost-equal-to 10 seconds; at -75 mV, recovery was practically absent. The absence of an important recovery at negative membrane potentials is consistent with the hypothesis of the drug being trapped in the channel. A limited frequency-dependent block could be demonstrated. Use-dependent unblock was demonstrated by a rapid recovery from block during stimulation following complete washout of the drug. It is concluded that almokalant shifts the activation curve of I(K) in the hyperpolarizing direction, blocks the open channel, and is trapped by the closure of the activation gate.
引用
收藏
页码:857 / 868
页数:12
相关论文
共 24 条