Wolfes Julian, Ellermann Christian, Broer Niklas, Rath Benjamin, Willy Kevin, Leitz Patrick Robert, Lange Philipp Sebastian, Eckardt Lars, Frommeyer Gerrit
Department of Cardiology II (Electrophysiology), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
Pharmaceuticals (Basel). 2020 Oct 20;13(10):321. doi: 10.3390/ph13100321.
The aim of this study was to investigate the effects of a combination of ranolazine with different selective inhibitors of the Na/Ca-exchanger (NCX) in an established experimental model of atrial fibrillation (AF). Eighteen hearts of New Zealand white rabbits were retrogradely perfused. Atrial catheters were used to record monophasic action potentials (aPRR). Hearts were paced at three different cycle lengths. Thereby, atrial action potential durations (aAPD), atrial effective refractory periods (aERP) and atrial post-repolarization refractoriness were obtained. Isoproterenol and acetylcholine were employed to increase the occurrence of AF. Thereafter, the hearts were assigned to two groups = 9 each group) and additionally perfused with a combination of 10 µM ranolazine and 1 µM of the selective NCX-inhibitor ORM-10103 (group A: Rano-ORM) or 10 µM ranolazine and 1 µM of another NCX-inhibitor, SEA0400 (group B: Rano-SEA). The infusion of Iso/ACh led to a shortening of aAPD, aERP, aPRR and the occurrence of AF episodes was significantly increased. Additional perfusion with ranolazine and ORM-10103 (group A) significantly prolonged the refractory periods and aPRR and AF episodes were effectively reduced. In group B, Rano-SEA led to a slight decrease in aAPD while aERP and aPRR were prolonged. The occurrence of AF episodes was consecutively reduced. To our knowledge, this is the first study investigating the effect of ranolazine combined with different selective NCX-inhibitors in an isolated whole-heart model of AF. Both combinations prolonged aERP and aPRR and thereby suppressed the induction of AF.
本研究的目的是在已建立的心房颤动（AF）实验模型中，研究雷诺嗪与不同的钠/钙交换体（NCX）选择性抑制剂联合使用的效果。对18只新西兰白兔的心脏进行逆行灌注。使用心房导管记录单相动作电位（aPRR）。以三种不同的周期长度对心脏进行起搏。由此获得心房动作电位持续时间（aAPD）、心房有效不应期（aERP）和心房复极化后不应期。使用异丙肾上腺素和乙酰胆碱来增加AF的发生率。此后，将心脏分为两组（每组n = 9），并额外灌注10 μM雷诺嗪与1 μM选择性NCX抑制剂ORM-10103的组合（A组：雷诺嗪-ORM）或10 μM雷诺嗪与1 μM另一种NCX抑制剂SEA0400的组合（B组：雷诺嗪-SEA）。输注异搏定/乙酰胆碱导致aAPD缩短，aERP缩短，AF发作的发生率显著增加。额外灌注雷诺嗪和ORM-10103（A组）可显著延长不应期和aPRR，并有效减少AF发作。在B组中，雷诺嗪-SEA导致aAPD略有下降，而aERP和aPRR延长。AF发作的发生率相继降低。据我们所知，这是第一项在AF离体全心模型中研究雷诺嗪与不同选择性NCX抑制剂联合作用的研究。两种组合均延长了aERP和aPRR，从而抑制了AF的诱发。
