Tsao P S, Aoki N, Lefer D J, Johnson G, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Circulation. 1990 Oct;82(4):1402-12. doi: 10.1161/01.cir.82.4.1402.
Myocardial ischemia and reperfusion have been shown to impair coronary vasorelaxation to endothelium-dependent vasodilators. To examine the time course of this dysfunction, occlusion of the left anterior descending (LAD) coronary artery (90 minutes) was followed by reperfusion for 0, 2.5, 5, 20, 180, or 270 minutes. Coronary arterial rings from the ischemic LAD and control left circumflex (LCx) arteries were tested for responsiveness to the endothelium-dependent receptor-mediated vasodilator, acetylcholine (ACh), and the endothelium-dependent nonreceptor-mediated vasodilator, A23187, as well as the endothelium-independent vasodilator, NaNO2. ACh relaxation was not impaired after 90 minutes of ischemia without reperfusion. However, 2.5 minutes of reperfusion resulted in depressed ACh responses (36 +/- 10% of control) that was further reduced to 16 +/- 6% at 20 minutes, and remained comparably depressed at every time thereafter. A23187 vasodilator responses were also attenuated after reperfusion, although the reduced response occurred later (that is, at 20 minutes). There was no significant decrease in response to NaNO2 in the LAD at any time or to any vasodilator in LCx control rings. Treatment with recombinant human superoxide dismutase (hSOD, 5 mg/kg/hr, that is, 15,545 SOD units/kg/hr), starting 10 minutes before reperfusion, preserved the vasodilator response to ACh (82 +/- 6%) and A23187, but treatment with the hydroxyl ion scavenger N-(2-mercapto proprionyl)-glycine (MPG) (8 mg/kg/hr) only protected the A23187 response. No damage to the surface of the endothelium was observed by scanning electron microscopy at any time point. Myocardial cell damage increased with time of reperfusion as assessed by increasing plasma CK activities and amounts of necrotic tissue indexed to area at risk. Significant myocardial injury occurred at 3 hours after reperfusion. These findings suggest that endothelial dysfunction resulting in reduced endothelium-derived relaxing factor release occurs before the development of myocardial cell necrosis and may be due to oxygen-derived free radicals produced rapidly on reperfusion.
心肌缺血和再灌注已被证明会损害冠状动脉对内皮依赖性血管舒张剂的血管舒张作用。为了研究这种功能障碍的时间进程，先将左前降支（LAD）冠状动脉闭塞90分钟，然后再灌注0、2.5、5、20、180或270分钟。检测来自缺血LAD和对照左旋支（LCx）动脉的冠状动脉环对内皮依赖性受体介导的血管舒张剂乙酰胆碱（ACh）、内皮依赖性非受体介导的血管舒张剂A23187以及内皮非依赖性血管舒张剂NaNO2的反应性。在缺血90分钟且无再灌注的情况下，ACh介导的舒张功能未受损。然而，再灌注2.5分钟导致ACh反应降低（为对照的36±10%），在20分钟时进一步降至16±6%，此后在每个时间点均保持相当程度的降低。再灌注后A23187的血管舒张反应也减弱，尽管反应降低出现得较晚（即在20分钟时）。LAD对NaNO2的反应在任何时间均无显著降低，LCx对照环对任何血管舒张剂的反应也无显著降低。在再灌注前10分钟开始用重组人超氧化物歧化酶（hSOD，5mg/kg/小时，即15545 SOD单位/kg/小时）治疗，可保留对ACh（82±6%）和A23187的血管舒张反应，但用羟基离子清除剂N-（2-巯基丙酰基）-甘氨酸（MPG）（8mg/kg/小时）治疗仅能保护对A23187的反应。在任何时间点通过扫描电子显微镜均未观察到内皮表面有损伤。通过血浆肌酸激酶活性增加以及以危险区域面积为指标的坏死组织量增加来评估，心肌细胞损伤随再灌注时间延长而增加。再灌注3小时后出现明显的心肌损伤。这些发现表明，导致内皮源性舒张因子释放减少的内皮功能障碍发生在心肌细胞坏死之前，可能是由于再灌注时迅速产生的氧衍生自由基所致。
