Amran Md Shah, Hashimoto Keitaro, Homma Nobuo
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho, Nakakoma, Yamanashi, Japan.
J Pharmacol Exp Ther. 2004 Jul;310(1):83-9. doi: 10.1124/jpet.104.066951. Epub 2004 Mar 17.
The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 microM) suppressed abnormal electrical activity induced by aconitine, but SEA (100 microM) did not show such effects. KBR (10 microM) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 microM) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na+ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.
钠钙交换体（NCX）在调节心脏收缩性和电活动方面起着关键作用。然而，NCX阻滞剂对室性心律失常的影响仍存在争议。我们使用心电图记录和电流钳法，研究了两种NCX阻滞剂KB-R7943（KBR）和SEA0400（SEA）对乌头碱诱导的豚鼠心律失常的影响。使用Luo和Rudy的心室肌细胞计算机模型（1991年《循环研究》68:1501 - 1526），我们模拟了NCX抑制产生的异常膜活动。在整体动物模型中，1至30 mg/kg（静脉注射）剂量范围内的KBR可剂量依赖性地抑制乌头碱诱导的心律失常，但10 mg/kg的SEA不能抑制这些心律失常。在分离的心室肌细胞中也存在差异。KBR（10 μM）可抑制乌头碱诱导的异常电活动，但SEA（100 μM）未显示出此类作用。KBR（10 μM）显著改变了动作电位形态（复极化50%时的动作电位时程），但SEA（1 - 100 μM）未改变这些形态。在计算机模拟研究中，乌头碱诱导的异常电活动通过Na⁺通道动力学的负向移位模拟，随后NCX活性额外抑制90%（模拟NCX抑制剂的作用），这增强了异常膜活动。我们的结果表明，KBR而非SEA对乌头碱诱导的心律失常的抑制可能源于NCX抑制以外的机制，因此NCX系统在乌头碱诱导的心律失常中所起作用不大。
