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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >L-364,373 (R-L3) enantiomers have opposite modulating effects on Iks in mammalian ventricular myocytes
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L-364,373 (R-L3) enantiomers have opposite modulating effects on Iks in mammalian ventricular myocytes

机译：L-364,373（R-L3）对映异构体对哺乳动物心室肌细胞中Iks的调节作用相反

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摘要

Activators of the slow delayed rectifier K+ current (IKs) have been suggested as promising tools for suppressing ventricular arrhythmias due to prolongation of repolarization. Recently, L-364,373 (R-L3) was nominated to activate IKs in myocytes from several species; however, in some studies, it failed to activate IKs. One later study suggested opposite modulating effects from the R-L3 enantiomers as a possible explanation for this discrepancy. Therefore, we analyzed the effect of the RL-3 enantiomers on IKs in ventricular mammalian myocytes, by applying standard microelectrode and whole-cell patch-clamp techniques at 37 °C. We synthesized 2 substances, ZS_1270B (right) and ZS_1271B (left), the 2 enantiomers of R-L3. In rabbit myocytes, ZS_1270B enhanced the IKs tail current by approximately 30%, whereas ZS_1271B reduced IKs tails by 45%. In guinea pig right ventricular preparations, ZS_1270B shortened APD90 (action potential duration measured at 90% repolarization) by 12%, whereas ZS_1271B lengthened it by approximately 15%. We concluded that R-L3 enantiomers in the same concentration range indeed have opposite modulating effects on IKs, which may explain why the racemic drug R-L3 previously failed to activate IKs. ZS_1270B is a potent IKs activator, therefore, this substance is appropriate to test whether IKs activators are ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials.
机译：缓慢延迟的整流器K +电流（IKs）的激活剂已被认为是抑制心律失常的有效手段，因为复极化时间延长。最近，提名L-364,373（R-L3）激活几种物种的肌细胞中的IK。但是，在某些研究中，它无法激活IK。后来的一项研究表明，R-L3对映体具有相反的调节作用，可以解释这种差异。因此，我们通过在37°C下应用标准微电极和全细胞膜片钳技术，分析了RL-3对映异构体对心室哺乳动物心肌细胞IK的影响。我们合成了2种物质，即R-L3的2个对映异构体ZS_1270B（右）和ZS_1271B（左）。在兔心肌细胞中，ZS_1270B将IKs尾电流提高了约30％，而ZS_1271B将IKs尾电流降低了45％。在豚鼠右心室制剂中，ZS_1270B将APD90（在90％复极状态下测量的动作电位持续时间）缩短了12％，而ZS_1271B将其延长了约15％。我们得出的结论是，相同浓度范围内的R-L3对映异构体确实对IK具有相反的调节作用，这可以解释为什么外消旋药物R-L3以前未能激活IK。 ZS_1270B是一种有效的IKs激活剂，因此，该物质适合测试IKs激活剂是否是抑制源自动作电位延长的室性心律失常的理想工具。

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