Chiang Chern-En, Luk Hsiang-Ning, Wang Tsui-Min, Ding Philip Yu-An
Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, 201, Sec 2, Shih-Pai Road, 112, Taipei, Taiwan.
Cardiovasc Res. 2002 Aug 1;55(2):290-9. doi: 10.1016/s0008-6363(02)00438-8.
Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization.
We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs.
Action potential duration at 90% repolarization (APD(90)) was not affected by sildenafil in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg).
Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L).
服用西地那非的患者偶尔会有猝死的报道。本研究的目的是调查西地那非对心脏复极化的影响。
我们在分离的豚鼠乳头肌和犬浦肯野纤维中使用传统微电极记录技术，在豚鼠心室肌细胞中使用全细胞膜片钳技术，并在豚鼠体内进行心电图测量。
在治疗浓度（≤1微摩尔）下，西地那非对90%复极化时的动作电位时程（APD(90)）无影响，但在豚鼠乳头肌和犬浦肯野纤维中，较高浓度（≥10微摩尔）会使其缩短。D-索他洛尔在相同制剂中浓度≥1微摩尔时以反向频率依赖性方式延长APD(90)。联合使用西地那非（10和30微摩尔）可消除D-索他洛尔（30微摩尔）和胺碘酮（100微摩尔）对APD的延长作用。浓度高达30微摩尔的西地那非对豚鼠心室肌细胞延迟整流钾电流的快速成分（I(Kr)）和慢速成分（I(Ks)）均无显著影响。西地那非剂量依赖性地阻断豚鼠心室肌细胞的L型钙电流（I(Ca,L)），但对持续性钠电流无影响。完整豚鼠的心电图记录显示，口服西地那非（10和30毫克/千克）可使QTc间期显著缩短。西地那非（30毫克/千克）可消除D,L-索他洛尔（50毫克/千克）和胺碘酮（100毫克/千克）对QT的延长作用。
西地那非不会延长心脏复极化。相反，在超治疗浓度下，它可能通过对I(Ca,L)的阻断作用加速心脏复极化。
