Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with IKATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD90-Epi, MAPD90-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD90-Epi, MAPD90-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ2=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ2=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.
目的: 探讨抑制晚钠电流的药物对短QT间期心脏可能的电生理作用及其机制。 方法: 采用Langendorff灌流装置制备兔离体心脏电生理研究模型。选择新西兰大耳白兔80只,首先任意选取34只,未用药时为对照A组(n=34)、给予IKATP开放剂吡那地尔后为吡那地尔A组(n=34),再从吡那地尔A组中选取27只,联用钠通道抑制剂或传统的用于治疗短QT综合征的药物奎尼丁后分为雷诺嗪联用组(n=9)、美西律联用组(n=9)、奎尼丁联用组(n=9)。在剩余的46只新西兰兔中选取19只,未用药时为对照B组(n=19),给予吡那地尔后为吡那地尔B组(n=19)。其余27只分为雷诺嗪单用组(n=9)、美西律单用组(n=9)、奎尼丁单用组(n=9)。采集对照A组、吡那地尔A组的心电生理参数,在对照B组、吡那地尔B组中采用程序电刺激诱发室性心律失常并采集心电图。采集吡那地尔联用组和单用药物组的心电生理参数,同时诱发室性心律失常并采集心电图。吡那地尔、雷诺嗪、美西律、奎尼丁药物浓度分别为30、10、30、1 μmol/L。 结果: 与对照A组相比,吡那地尔A组的QT间期、心外膜和心内膜动作电位复极化完成90%处的时程(MAPD90)缩短、跨室壁复极离散度(TDR)增大、有效不应期(ERP)和复极后不应期(PRR)降低(P<0.05)。与吡那地尔A组相比,美西律联用组、奎尼丁联用组心外膜和心内膜MAPD90和QT间期延长(P<0.05),雷诺嗪联用组则不发生改变;TDR在3个联用组均显著降低,但ERP和PRR则延长(P<0.05)。程序电刺激时对照B组室性心律失常诱发率为0,吡那地尔B组升高至10/19(χ²=13.6,P<0.05)。雷诺嗪联用组、美西律联用组和奎尼丁联用组室性心律失常的诱发率分别为1/9、1/9和0,均低于吡那地尔B组(χ²=4.5、4.5、7.4,P均<0.05)。 结论: 在QT间期缩短的心脏,抑制晚钠电流不会加重电生理异常,而且会降低恶性心律失常发生的危险性,其机制与逆转短QT情况下TDR的增大和不应期(包括ERP及PRR)的缩短有关。.