Knight D R, Smith A H, Flynn D M, MacAndrew J T, Ellery S S, Kong J X, Marala R B, Wester R T, Guzman-Perez A, Hill R J, Magee W P, Tracey W R
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Pfizer Inc., 3125 Eastern Point Road, Groton, CT 06340, USA.
J Pharmacol Exp Ther. 2001 Apr;297(1):254-9.
The cardioprotective efficacy of zoniporide (CP-597,396), a novel, potent, and selective inhibitor of the sodium-hydrogen exchanger isoform 1 (NHE-1), was evaluated both in vitro and in vivo using rabbit models of myocardial ischemia-reperfusion injury. In these models, myocardial injury was elicited with 30 min of regional ischemia and 120 min of reperfusion. Zoniporide elicited a concentration-dependent reduction in infarct size (EC(50) of 0.25 nM) in the isolated heart (Langendorff) and reduced infarct size by 83% (50 nM). This compound was 2.5- to 20-fold more potent than either eniporide or cariporide (EC(50) of 0.69 and 5.11 nM, respectively), and reduced infarct size to a greater extent than eniporide (58% reduction in infarct size). In open-chest, anesthetized rabbits, zoniporide also elicited a dose-dependent reduction in infarct size (ED(50) of 0.45 mg/kg/h) and inhibited NHE-1-mediated platelet swelling (maximum inhibition 93%). Furthermore, zoniporide did not cause any in vivo hemodynamic (mean arterial pressure, heart rate, rate pressure product) changes. Zoniporide represents a novel class of potent NHE-1 inhibitors with potential utility for providing clinical cardioprotection.
使用兔心肌缺血再灌注损伤模型，在体外和体内对新型、强效且选择性的钠氢交换体1（NHE-1）抑制剂唑尼泊酯（CP-597,396）的心脏保护功效进行了评估。在这些模型中，通过30分钟的局部缺血和120分钟的再灌注引发心肌损伤。唑尼泊酯在离体心脏（Langendorff）中引起梗死面积呈浓度依赖性减小（半数有效浓度[EC(50)]为0.25 nM），并使梗死面积减小83%（50 nM）。该化合物的效力比依尼泊酯或卡立泊洛分别强2.5至20倍（EC(50)分别为0.69和5.11 nM），且使梗死面积减小的程度大于依尼泊酯（梗死面积减小58%）。在开胸麻醉的兔中，唑尼泊酯也引起梗死面积呈剂量依赖性减小（半数有效剂量[ED(50)]为0.45 mg/kg/h），并抑制NHE-1介导的血小板肿胀（最大抑制率93%）。此外，唑尼泊酯未引起任何体内血流动力学（平均动脉压、心率、率压乘积）变化。唑尼泊酯代表了一类新型的强效NHE-1抑制剂，并具有提供临床心脏保护的潜在效用。
