Delyani J A, Nossuli T O, Scalia R, Thomas G, Garvey D S, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
J Pharmacol Exp Ther. 1996 Dec;279(3):1174-80.
S-Nitrosylated tissue plasminogen activator (tPA) is formed by S-nitrosylation of the clinically important agent tPA by nitric oxide, thus conferring nitric oxide donor properties to the molecule. Cats were subjected to 90 min of myocardial ischemia and 270 min of reperfusion and were treated with either tPA or S-nitrosylated tPA 10 min before reperfusion. S-Nitrosylated tPA-treated cats demonstrated marked attenuation of cardiac necrosis after myocardial ischemia/reperfusion, compared with cats receiving only tPA (13 +/- 3% vs. 28 +/- 3%, P < .01). Relaxation of ischemic/reperfused left anterior descending coronary artery rings in response to the endothelium-dependent dilators acetylcholine and A23187 was greater in the S-nitrosylated tPA-treated group, compared with the cats receiving only tPA, indicating that coronary vascular endothelial function was preserved by S-nitrosylated tPA. S-Nitrosylated tPA also resulted in markedly reduced adherence of neutrophils to the coronary vascular endothelium, compared with nonnitrosylated tPA (P < .01). Immunohistochemical localization of P-selectin in the ischemic region was also significantly reduced by S-nitrosylated tPA, compared with the control group (P < .01). These data indicate that S-nitrosylated tPA is a cardioprotective agent, likely exerting its effect by site-specific nitric oxide donation resulting in inhibition of neutrophil-endothelium interaction via a P-selectin-dependent mechanism.
S-亚硝基化组织型纤溶酶原激活剂（tPA）由一氧化氮对临床上重要的药物tPA进行S-亚硝基化形成，从而赋予该分子一氧化氮供体特性。猫经历90分钟的心肌缺血和270分钟的再灌注，并在再灌注前10分钟用tPA或S-亚硝基化tPA进行治疗。与仅接受tPA治疗的猫相比，接受S-亚硝基化tPA治疗的猫在心肌缺血/再灌注后心脏坏死明显减轻（13±3%对28±3%，P<.01）。与仅接受tPA治疗的猫相比，S-亚硝基化tPA治疗组中缺血/再灌注的左前降支冠状动脉环对内皮依赖性舒张剂乙酰胆碱和A23187的舒张反应更大，表明S-亚硝基化tPA可保留冠状动脉血管内皮功能。与未亚硝基化的tPA相比，S-亚硝基化tPA还导致中性粒细胞与冠状动脉血管内皮的粘附明显减少（P<.01）。与对照组相比，S-亚硝基化tPA还显著降低了缺血区域P-选择素的免疫组化定位（P<.01）。这些数据表明，S-亚硝基化tPA是一种心脏保护剂，可能通过位点特异性一氧化氮供体发挥作用，通过P-选择素依赖性机制抑制中性粒细胞与内皮的相互作用。
