Hennan James K, Swillo Robert E, Morgan Gwen A, Keith James C, Schaub Robert G, Smith Robert P, Feldman Hal S, Haugan Ketil, Kantrowitz Joel, Wang Phil J, Abu-Qare Aqel, Butera John, Larsen Bjarne D, Crandall David L
Wyeth Research, Philadelphia, PA 19101.
J Pharmacol Exp Ther. 2006 Apr;317(1):236-43. doi: 10.1124/jpet.105.096933. Epub 2005 Dec 12.
The antiarrhythmic and cardioprotective effect of increasing gap junction intercellular communication during ischemia/reperfusion injury has not been studied. The antiarrhythmic peptide rotigaptide (previously ZP123), which maintains gap junction intercellular communication, was tested in dogs subjected to a 60-min coronary artery occlusion and 4 h of reperfusion. Rotigaptide was administered i.v. 10 min before reperfusion as a bolus + i.v. infusion at doses of 1 ng/kg bolus + 10 ng/kg/h infusion (n = 6), 10 ng/kg bolus + 100 ng/kg/h infusion (n = 5), 100 ng/kg bolus + 1000 ng/kg/h infusion (n = 8), 1000 ng/kg bolus + 10 mug/kg/h infusion (n = 6), and vehicle control (n = 5). Premature ventricular complexes (PVCs) were quantified during reperfusion. A series of four or more consecutive PVCs was defined as ventricular tachycardia (VT). The total incidence of VT was reduced significantly with the two highest doses of rotigaptide (20.3 +/- 10.9 and 4.3 +/- 4.1 events; p < 0.05) compared with controls (48.7 +/- 6.0). Total PVCs were reduced significantly from 25.1 +/- 4.2% in control animals to 11.0 +/- 4.4 and 1.7 +/- 1.3% after the two highest doses of rotigaptide. Infarct size, expressed as a percentage of the left ventricle, was reduced significantly from 13.2 +/- 1.9 in controls to 7.1 +/- 1.0 (p < 0.05) at the highest dose of rotigaptide. Ultrastructural evaluation revealed no differences in myocardial injury in the infarct area, area at risk, border zone, or normal zone in vehicle and rotigaptide-treated animals. However, rotigaptide did increase the presence of gap junctions in the area at risk (p = 0.022, Fisher's exact test). Rotigaptide had no effect on heart rate, blood pressure, heart rate-corrected QT interval, or left ventricular end-diastolic pressure. In conclusion, these results demonstrate that rotigaptide is a potent antiarrhythmic compound with cardioprotective effects and desirable safety.
缺血/再灌注损伤期间增加缝隙连接细胞间通讯的抗心律失常和心脏保护作用尚未得到研究。维持缝隙连接细胞间通讯的抗心律失常肽罗替加肽（以前称为ZP123）在经历60分钟冠状动脉闭塞和4小时再灌注的犬中进行了测试。罗替加肽在再灌注前10分钟静脉推注给药 + 静脉输注，剂量为1 ng/kg推注 + 10 ng/kg/h输注（n = 6）、10 ng/kg推注 + 100 ng/kg/h输注（n = 5）、100 ng/kg推注 + 1000 ng/kg/h输注（n = 8）、1000 ng/kg推注 + 10 μg/kg/h输注（n = 6），以及溶剂对照（n = 5）。在再灌注期间对室性早搏（PVC）进行定量。一系列四个或更多连续的PVC被定义为室性心动过速（VT）。与对照组（48.7±6.0）相比，两种最高剂量的罗替加肽使VT的总发生率显著降低（20.3±10.9和4.3±4.1次事件；p<0.05）。两种最高剂量的罗替加肽给药后，总PVC从对照动物的25.1±4.2%显著降低至11.0±4.4%和1.7±1.3%。以左心室百分比表示的梗死面积在罗替加肽最高剂量时从对照组的13.2±1.9显著降低至7.1±1.0（p<0.05）。超微结构评估显示，溶剂和罗替加肽治疗动物的梗死区域、危险区域、边缘区或正常区的心肌损伤无差异。然而，罗替加肽确实增加了危险区域缝隙连接的存在（p = 0.022，Fisher精确检验）。罗替加肽对心率、血压、心率校正的QT间期或左心室舒张末期压力无影响。总之，这些结果表明罗替加肽是一种具有心脏保护作用且安全性良好的强效抗心律失常化合物。
