拉西地平对豚鼠心室肌细胞L型钙通道的阻滞特性。

Characteristics of L-type calcium channel blockade by lacidipine in guinea-pig ventricular myocytes.

作者信息

Cerbai E, Giotti A, Mugelli A

机构信息

Department of Pharmacology, University of Firenze, Italy.

出版信息

Br J Pharmacol. 1997 Feb;120(4):667-75. doi: 10.1038/sj.bjp.0700951.

DOI:10.1038/sj.bjp.0700951

PMID:9051306

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1564510/

Abstract

The Ca(2+)-antagonistic properties of lacidipine were investigated in patch-clamp guinea-pig ventricular myocytes. 2. In basal conditions, 0.1 microM lacidipine reduced the action potential duration, associated with a decrease in the L-type calcium current (ICa,L) to 66 +/- 4% of the control value, without a change in the current-voltage relationship. Sodium current and background potassium currents were not affected. All the effects reached a steady state within 2 min. 3. The Ca(2+)-antagonistic effect of lacidipine was voltage-dependent: a marked negative shift (about 20 mV) of the steady-state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) prepulses. 4. The onset of and recovery from the voltage-dependent effect caused by 0.1 microM lacidipine were significantly slower when compared to those of equiactive concentrations of nimodipine (0.5 microM) and nisoldipine (0.1 microM). ICa,L measured after prepulses at -40 mV lasting 500 ms or less was unchanged (95 +/- 5% of maximum current value) while it was reduced to 49 +/- 10% by nimodipine and 43 +/- 9% by nisoldipine (P < 0.05 vs lacidipine for both). 5. Similarly, the recovery from block in the presence of lacidipine was slower than with nimodipine and nisoldipine. After a prepulse of 1 s at -80 mV, ICa,L recovered up to 54 +/- 2% of the maximum current value in the presence of lacidipine, and up to 91 +/- 3% and 93 +/- 5% in the presence of nimodipine and nisoldipine, respectively (P < 0.05 vs lacidipine). 6. Blockade of ICa,L by lacidipine was use-dependent. After ten 200 ms long pulses (1 Hz) from -80 mV, ICa,L was reduced to 55 +/- 7% of the current measured at the first pulse. In the presence of nimodipine and nisoldipine, ICa,L elicited by the tenth pulse amounted to 93 +/- 3% and 80 +/- 6% of the first pulse value, respectively (P < 0.05 vs lacidipine). Lacidipine did not cause use-dependent blockade of ICa,L in cells stimulated with 10 ms long pulses. 7. These results demonstrate that lacidipine selectively inhibits ICa,L in isolated cardiomyocytes and suggest that this effect occurs mainly through binding to the inactivated Ca2+ channels.

摘要

在膜片钳豚鼠心室肌细胞中研究了拉西地平的钙拮抗特性。2. 在基础条件下，0.1微摩尔/升拉西地平可缩短动作电位时程，同时L型钙电流（ICa,L）降低至对照值的66±4%，而电流-电压关系无变化。钠电流和背景钾电流不受影响。所有效应在2分钟内达到稳态。3. 拉西地平的钙拮抗作用具有电压依赖性：用长（10秒）的预处理脉冲时，观察到稳态失活曲线有明显的负向移位（约20毫伏），而用短（350毫秒）的预处理脉冲时则没有。4. 与等活性浓度的尼莫地平（0.5微摩尔/升）和尼索地平（0.1微摩尔/升）相比，0.1微摩尔/升拉西地平引起的电压依赖性效应的起效和恢复明显较慢。在-40毫伏持续500毫秒或更短时间的预处理脉冲后测量的ICa,L未改变（为最大电流值的95±5%），而尼莫地平使其降低至49±10%，尼索地平使其降低至43±9%（两者与拉西地平相比，P<0.05）。5. 同样，在存在拉西地平时的阻断恢复也比尼莫地平和尼索地平慢。在-80毫伏进行1秒的预处理脉冲后，在存在拉西地平时ICa,L恢复至最大电流值的54±2%，在存在尼莫地平和尼索地平时分别恢复至91±3%和93±5%（与拉西地平相比，P<0.05）。6. 拉西地平对ICa,L的阻断具有使用依赖性。从-80毫伏进行十个200毫秒长的脉冲（1赫兹）后，ICa,L降低至第一个脉冲时测量电流的55±7%。在存在尼莫地平和尼索地平时，第十个脉冲引发的ICa,L分别为第一个脉冲值的93±3%和80±6%（两者与拉西地平相比，P<0.05）。拉西地平在用10毫秒长的脉冲刺激的细胞中不会引起ICa,L的使用依赖性阻断。7. 这些结果表明，拉西地平在分离的心肌细胞中选择性抑制ICa,L，并提示这种效应主要通过与失活的钙通道结合而发生。