Jost Norbert, Virág László, Bitay Miklós, Takács János, Lengyel Csaba, Biliczki Péter, Nagy Zsolt, Bogáts Gábor, Lathrop David A, Papp Julius G, Varró András
Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720 Szeged, Hungary.
Circulation. 2005 Sep 6;112(10):1392-9. doi: 10.1161/CIRCULATIONAHA.105.550111. Epub 2005 Aug 29.
Although pharmacological block of the slow, delayed rectifier potassium current (IKs) 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.
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 micromol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 micromol/L) produced a <12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the IKr 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 (IKr) 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 (IKs) 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 IKs was significantly increased (49.6+/-7.24 pA; n=10). On application of an "action potential-like" test pulse, IKr increased as voltage became more negative, whereas IKs 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 micromol/L adrenaline, 1 micromol/L HMR-1556 significantly increased APD by 14.7+/-3.2% (P<0.05; n=3).
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.
尽管苯并二氢吡喃醇293B、L - 735,821或HMR - 1556对缓慢、延迟整流钾电流（IKs）的药理学阻断对离体兔和犬心室肌细胞的动作电位时程（APD）影响很小，但IKs阻断对正常人心室肌APD的影响尚不清楚。因此，进行了多项研究以阐明IKs在正常人心室肌以及在外源性多非利特和肾上腺素使复极储备减弱且交感神经激活增强的制剂中的作用。
取自未患病器官捐献者的标本。使用传统微电极技术在心室小梁和乳头肌中测量动作电位；使用电压钳技术在心室肌细胞中测量膜电流。在300至5000毫秒的周期长度起搏时，苯并二氢吡喃醇293B（10微摩尔/升）、L - 735,821（100纳摩尔/升）和HMR - 1556（100纳摩尔/升和1微摩尔/升）使APD变化<12毫秒，而IKr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和苯并二氢吡喃醇293B在存在E - 4031以阻断IKr的情况下均阻断IKs。在向30毫伏施加150毫秒长的测试脉冲结束时，E - 4031敏感电流（IKr）为32.9±6.7皮安（n = 8）；L - 735,821敏感电流（IKs）幅度为17.8±2.94皮安（n = 10）。在更长的500毫秒测试脉冲期间，IKr没有显著变化（33.6±6.1皮安；n = 8），而IKs显著增加（49.6±7.24皮安；n = 10）。施加“动作电位样”测试脉冲时，IKr随着电压变得更负而增加，而IKs在动作电位样测试脉冲的所有阶段都保持较小。在首先用50纳摩尔/升多非利特延长APD并通过1微摩尔/升肾上腺素增加交感神经激活的实验中，1微摩尔/升HMR - 1556使APD显著增加14.7±3.2%（P<0.05；n = 3）。
在没有交感神经刺激的情况下，药理学上的IKs阻断在增加正常人心室肌APD方面作用很小。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发挥着越来越重要的作用。
