Restricting excessive cardiac action potential and QT prolongation -: A vital role for IKs in human ventricular muscle
Restricting excessive cardiac action potential and QT prolongation -: A vital role for IKs in human ventricular muscle
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DOI：
10.1161/circulationaha.105.550111
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发表时间：
2005-09-06
期刊：
影响因子：
37.8
通讯作者：
Varró, A
中科院分区：
文献类型：
--
作者：
Jost, N;Virág, L;Varró, A
背景-虽然用色原烷醇293 B、L-735，821或HMR-1556药理学阻断慢延迟整流钾电流（I-Ks）对离体兔和犬心室肌细胞的动作电位时程（APD）几乎没有影响，但IKs阻断对正常人心室肌APD的影响尚不清楚。因此，进行了研究，以阐明IKs在正常人心室肌和制剂中的作用，其中复极储备衰减和交感神经激活增加外源性多非利特和adrenaline.Methods和结果-制剂从未患病的器官供体。采用常规微电极技术测量心室肌小梁和乳头肌的动作电位;采用电压钳技术测量心室肌细胞的膜电流。Chromanol 293 B（10 μ mol/L）、L-735，821（100 nmol/L）和HMR-1556（100 nmol/L和1 μ mol/L）在300 - 5000 ms周期长度起搏时，APD变化< 12 ms，而I-Kr阻断剂索他洛尔和E-4031显著延长APD。在电压钳实验中，L-735，821和色原烷醇293 B在E-4031存在下分别阻断IKs以阻断IKr。在150 ms长的测试脉冲结束时，E-4031敏感电流（I-Kr）为32.9 +/- 6.7 pA（n = 8）; L-735，821敏感电流（I-Ks）幅度为17.8 +/- 2.94 pA（n = 10）。在较长的500 ms测试脉冲期间，IKr基本上没有变化（33.6 +/- 6.1 pA; n = 8），I-Ks显著增加（49.6 +/- 7.24 pA; n = 10）。在施加“类动作电位”测试脉冲时，I-Kr随着电压变得更负而增加，而I-Ks在类动作电位测试脉冲的所有相位中保持较小。在实验中，50 nmol/L多非利特首先延长APD，1 μ mol/L肾上腺素增加交感神经激活，1 μ mol/L HMR-1556使APD显著增加14.7 +/- 3.2%（P < 0.05; n = 3）。然而，当人心室肌复极储备减弱时，IKs在限制动作电位延长方面起着越来越重要的作用。
Background - Although pharmacological block of the slow, delayed rectifier potassium current (I-Ks) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of IKs block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of IKs in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline.Methods and Results - Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 mu mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 mu mol/L) produced a < 12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I-Kr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L- 735,821 and chromanol 293B each blocked IKs in the presence of E-4031 to block IKr. The E-4031-sensitive current (I-Kr) at the end of a 150-ms-long test pulse to 30 mV was 32.9 +/- 6.7 pA (n = 8); the L-735,821-sensitive current (I-Ks) magnitude was 17.8 +/- 2.94 pA (n = 10). During a longer 500-ms test pulse, IKr was not substantially changed (33.6 +/- 6.1 pA; n = 8), and I-Ks was significantly increased (49.6 +/- 7.24 pA; n = 10). On application of an "action potential-like" test pulse, I-Kr increased as voltage became more negative, whereas I-Ks remained small throughout all phases of the action potential - like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 mu mol/L adrenaline, 1 mu mol/L HMR-1556 significantly increased APD by 14.7 +/- 3.2% (P < 0.05; n = 3).Conclusions - Pharmacological IKs block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, IKs plays an increasingly important role in limiting action potential prolongation.