新型NO供体SP/W-5186在兔心肌缺血/再灌注损伤中的作用和机制

Effect and possible mechanism of SP/W-5186, a newly developed NO donor, on myocardial ischemia/reperfusion injury

目的 :研究一种结构中含有半胱氨酸的新型一氧化氮供体 SP/ W- 5 186 ,在新西兰兔缺血 /再灌注心肌损伤中的作用和机制。方法 :兔缺血 45 min继之再灌注 180 min。再灌注前 5 min,通过静脉单剂量给予低剂量 (0 .3μmol/ kg)或高剂量 (1μm ol/ kg)的 SP/ W- 5 186。结果 :给予 0 .3μm ol/ kg SP/ W- 5 186对平均动脉压、心率等心功能指标没有影响 ,可显著地降低血小板聚集 ,减少白细胞聚集。类似物 SP/ W- 6 373则不产生任何保护作用。结论 :由 SP/ W- 5 186中释放的 NO可显著地保护心肌组织 ,减轻再灌注损伤。作用机制包括抑制血小板聚集 ,减少

AIM: To investigate the effects of different doses of SP/W 5186, a cysteine containing nitric oxide donor, on myocardial cellular injury associated with ischemia/reperfusion and possible mechanism by which SP/W 5186 may exert its cardioprotective effects. METHODS: The effects of SP/W 5186 on myocardial reperfusion injury were studied in a rabbit ischemia (45 min) and reperfusion (180 min) model. At 5 min before reperfusion, the rabbits were randomly assigned to one of the following 6 groups. Each drug or vehicle was given as a single intravenous bolus injection over 1 min. The effects of SP/W 5186 on cardiac functional, myocardial cellular injury, neutrophil accumulation in the myocardial tissue, myocardial lipid peroxidation, neutrophil adhesion to cultured microvessel endothelial cells, coronary endothelial function, myocardial malondialdehyde content and platelet aggregation were determined before and after ischemia/reperfusion. RESULTS: Administration of low dose SP/W 5186 exerted marked cardioprotective effects as evidenced by improved cardiac functional recovery ( P <0 05 vs vehicle), decreased plasma creatine kinase concentration ( P <0 01) and reduced myocardial infarct size ( P <0 01), significantly decreased platelet aggregation ( P <0 01 vs vehicle), attenuated polymorphonuclear neutrophilic accumulation in myocardial tissue, inhibited PMN adhesion to endothelial cells and preserved endothelial function, and did not change mean arterial blood pressure, heart rate. CONCLUSION: These results demonstrate that NO released from SP/W 5186 can significantly protect myocardial tissue from reperfusion injury. The primary mechanisms of the observed cardioprotection by the SP/W 5186 involve inhibition of platelet aggregation, attenuation of PMN endothelium interaction and preservation of endothelial function.