Liu G L, Christopher T A, Lopez B L, Gao F, Guo Y, Gao E, Knuettel K, Feelisch M, Ma X L
Division of Emergency Medicine, Thomas Jefferson University, Monheim, Germany.
J Pharmacol Exp Ther. 1998 Nov;287(2):527-37.
The effects of SP/W-5186, a cysteine-containing nitric oxide (.NO) donor, on myocardial reperfusion injury were studied in a rabbit ischemia (45 min) and reperfusion (180 min) model. Five min before reperfusion, either low-dose (0.3 micromol/kg) or high-dose (1 micromol/kg) SP/W-5186 was given intravenously as a bolus. Administration of 0.3 micromol/kg SP/W-5186 did not change mean arterial blood pressure, heart rate or pressure-rate index. However, administration of low-dose SP/W-5186 exerted marked cardioprotective effects as evidenced by improved cardiac functional recovery (P <.05 vs. vehicle), decreased plasma creatine kinase concentration (P <. 01) and reduced infarct size (P <.01). Moreover, administration of SP/W-5186 significantly decreased platelet aggregation (P <.01 vs. vehicle), attenuated polymorphonuclear leukocyte (PMN) accumulation in myocardial tissue, inhibited PMN adhesion to endothelial cells and preserved endothelial function. Administration of high-dose SP/W-5186 resulted in a transient but significant decrease in mean arterial blood pressure and exerted more cardiac protection compared with low-dose treatment. However, the effects on platelet aggregation, PMN accumulation and PMN adhesion did not differ significantly between the two SP/W-5186 groups. Furthermore, administration of SP/W-6373, an analogue of SP/W-5186 that lacks the NO moiety, failed to exert any protective effects. These results demonstrate that NO released from SP/W-5186 significantly protected myocardial tissue from reperfusion injury. The primary mechanisms of the observed cardioprotection by SP/W-5186 involve inhibition of platelet aggregation, attenuation of PMN-endothelium interaction and preservation of endothelial function.
在兔缺血（45分钟）再灌注（180分钟）模型中，研究了含半胱氨酸的一氧化氮（·NO）供体SP/W - 5186对心肌再灌注损伤的影响。再灌注前5分钟，静脉推注低剂量（0.3微摩尔/千克）或高剂量（1微摩尔/千克）的SP/W - 5186。给予0.3微摩尔/千克的SP/W - 5186不会改变平均动脉血压、心率或压力 - 心率指数。然而，低剂量SP/W - 5186给药具有显著的心脏保护作用，表现为心脏功能恢复改善（与赋形剂相比，P <.05）、血浆肌酸激酶浓度降低（P <.01）和梗死面积减小（P <.01）。此外，SP/W - 5186给药显著降低血小板聚集（与赋形剂相比，P <.01），减轻心肌组织中多形核白细胞（PMN）的积聚，抑制PMN与内皮细胞的粘附并保留内皮功能。给予高剂量SP/W - 5186导致平均动脉血压短暂但显著下降，与低剂量治疗相比具有更强的心脏保护作用。然而，两个SP/W - 5186组对血小板聚集、PMN积聚和PMN粘附的影响没有显著差异。此外，给予缺乏NO部分的SP/W - 5186类似物SP/W - 6373未能发挥任何保护作用。这些结果表明，SP/W - 5186释放的NO显著保护心肌组织免受再灌注损伤。SP/W - 5186观察到的心脏保护的主要机制包括抑制血小板聚集、减轻PMN - 内皮相互作用和保留内皮功能。
