Christ Torsten, Wettwer Erich, Wuest Melinda, Braeter Manfred, Donath Frank, Champeroux Pascal, Richard Serge, Ravens Ursula
Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Feb;376(6):431-40. doi: 10.1007/s00210-007-0231-1. Epub 2007 Dec 19.
Drugs that prolong the QT interval by blocking human ether-a-go-go (HERG) channels may enhance the risk of ventricular arrhythmia. The spasmolytic drug propiverine is widely used for the therapy of overactive bladder (OAB). Here, we have investigated the effects of propiverine on cardiac ion channels and action potentials as well as on contractile properties of cardiac tissue, in order to estimate its cardiac safety profile, because other drugs used in this indication had to be withdrawn due to safety reasons. Whole-cell patch clamp technique was used to record the following cardiac ion currents: rapidly and slowly activating delayed rectifier K+ current (I(Kr), I(Ks)), ultra rapidly activating delayed rectifier K+ current (I(Kur)), inwardly rectifying K+ current I(K1), transient outward K+ current (I(to)), and L-type Ca2+ current (I(Ca,L)). Action potentials in cardiac tissue biopsies were recorded with conventional microelectrodes. The torsade de pointes screening assay (TDPScreen) was used for drug scoring. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native I(Kr) current in ventricular myocytes of guinea pig (IC50 values: 10 microM and 1.8 microM respectively). At high concentrations (100 microM), propiverine suppressed I(Ks). I(K1) and the transient outward current I(to) and I(Kur) were not affected. In guinea-pig ventricular and human atrial myocytes, propiverine also blocked I(Ca,L) (IC50 values: 34.7 microM and 41.7 microM, respectively) and reduced force of contraction. Despite block of I(Kr), action potential duration was not prolonged in guinea-pig and human ventricular tissue, but decreased progressively until excitation failed altogether. Similar effects were observed in dog Purkinje fibers. Propiverine obtained a low score in the TDPScreen. In conclusion, in vitro and in vivo studies of propiverine do not provide evidence for an enhanced cardiovascular safety risk. We propose that lack of torsadogenic risk of propiverine is related to enhancement of repolarization reserve by block of I(Ca,L).
通过阻断人醚 - 去极化相关基因（HERG）通道来延长QT间期的药物可能会增加室性心律失常的风险。解痉药丙哌维林被广泛用于治疗膀胱过度活动症（OAB）。在此，我们研究了丙哌维林对心脏离子通道、动作电位以及心脏组织收缩特性的影响，以评估其心脏安全性，因为该适应症中使用的其他药物因安全原因已被撤市。采用全细胞膜片钳技术记录以下心脏离子电流：快速和缓慢激活延迟整流钾电流（I(Kr)、I(Ks)）、超快速激活延迟整流钾电流（I(Kur)）、内向整流钾电流I(K1)、瞬时外向钾电流（I(to)）和L型钙电流（I(Ca,L)）。用传统微电极记录心脏组织活检中的动作电位。采用尖端扭转型室速筛选试验（TDPScreen）对药物进行评分。丙哌维林以浓度依赖性方式阻断HEK293细胞中表达的HERG通道以及豚鼠心室肌细胞中的天然I(Kr)电流（IC50值分别为10 microM和1.8 microM）。在高浓度（100 microM）时，丙哌维林抑制I(Ks)。I(K1)和瞬时外向电流I(to)以及I(Kur)不受影响。在豚鼠心室和人心房肌细胞中，丙哌维林也阻断I(Ca,L)（IC50值分别为34.7 microM和41.7 microM）并降低收缩力。尽管I(Kr)被阻断，但在豚鼠和人的心室组织中动作电位持续时间并未延长，而是逐渐缩短直至完全失去兴奋。在犬浦肯野纤维中也观察到类似效应。丙哌维林在TDPScreen中得分较低。总之，丙哌维林的体外和体内研究未提供心血管安全风险增加的证据。我们认为丙哌维林缺乏致尖端扭转型室速风险与通过阻断I(Ca,L)增强复极储备有关。
