Selective Na+/Ca2+ exchanger inhibition prevents Ca2+ overload-induced triggered arrhythmias
Selective Na+/Ca2+ exchanger inhibition prevents Ca2+ overload-induced triggered arrhythmias
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DOI：
10.1111/bph.12867
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发表时间：
2014-12-01
影响因子：
7.3
通讯作者：
Toth, Andras
中科院分区：
文献类型：
--
作者：
Nagy, Norbert;Kormos, Anita;Toth, Andras
背景和目的钠/钙交换器(NCX)活性增强可能在心律失常的发生中起重要作用；然而，关于NCX抑制抗心律失常效果的数据尚有争议。可行的解释可能是NCX抑制剂的选择性不令人满意和/或实验模型对Ca-i(2+)超载程度的依赖。因此，我们使用NCX抑制剂SEA0400和更具选择性的ORM10103来评估NCX抑制通过激活晚期钠电流(I-NAL)或抑制Na+/K+泵而增加[Ca~(2+)](I)的条件下对致心律失常的Ca-i(2+)升高的抑制作用。采用全细胞膜片钳技术测定心肌细胞NCX电流(I-NCX)。用钙离子敏感的荧光染料Fluo-4监测钙离子瞬变(CATS)。关键结果增强的i-NAL增加了钙负荷和AP时程。SEA0400和ORM10103可抑制I-NCX和阻止/逆转海葵毒素II(ATX-II)诱导的[Ca~(2+)](I)升高，但不影响时程、CAT和细胞的缩短，也不影响ATX-II引起的时程延长。ORM10103可显著减少Strophanthidin引起的舒张期自发钙释放事件的数目；然而，SEA0400不能限制藜芦碱引起的浦肯野-心室动作电位离散度的增加。结论和意义选择性的NCX抑制--可能是通过阻断I-rev(Ncx)(反向模式Ncx电流)--对[Na+](I)诱导的[Ca+](I)升高引起的心律失常有效，而不影响AP的波形。因此，选择性地抑制I-NCX，通过显著降低钙离子通道引起的致心律失常触发活性，可以被认为是一种很有前途的抗心律失常治疗策略。
Background and PurposeAugmented Na+/Ca2+ exchanger (NCX) activity may play a crucial role in cardiac arrhythmogenesis; however, data regarding the anti-arrhythmic efficacy of NCX inhibition are debatable. Feasible explanations could be the unsatisfactory selectivity of NCX inhibitors and/or the dependence of the experimental model on the degree of Ca-i(2+) overload. Hence, we used NCX inhibitors SEA0400 and the more selective ORM10103 to evaluate the efficacy of NCX inhibition against arrhythmogenic Ca-i(2+) rise in conditions when [Ca2+](i) was augmented via activation of the late sodium current (I-NaL) or inhibition of the Na+/K+ pump.Experimental ApproachAction potentials (APs) were recorded from canine papillary muscles and Purkinje fibres by microelectrodes. NCX current (I-NCX) was determined in ventricular cardiomyocytes utilizing the whole-cell patch clamp technique. Ca-i(2+) transients (CaTs) were monitored with a Ca2+-sensitive fluorescent dye, Fluo-4.Key ResultsEnhanced I-NaL increased the Ca2+ load and AP duration (APD). SEA0400 and ORM10103 suppressed I-NCX and prevented/reversed the anemone toxin II (ATX-II)-induced [Ca2+](i) rise without influencing APD, CaT or cell shortening, or affecting the ATX-II-induced increased APD. ORM10103 significantly decreased the number of strophanthidin-induced spontaneous diastolic Ca2+ release events; however, SEA0400 failed to restrict the veratridine-induced augmentation in Purkinje-ventricle APD dispersion.Conclusions and ImplicationsSelective NCX inhibition - presumably by blocking I-rev(NCX) (reverse mode NCX current) - is effective against arrhythmogenesis caused by [Na+](i)-induced [Ca2+](i) elevation, without influencing the AP waveform. Therefore, selective I-NCX inhibition, by significantly reducing the arrhythmogenic trigger activity caused by the perturbed Ca-i(2+) handling, should be considered as a promising anti-arrhythmic therapeutic strategy.