Takano H, Manchikalapudi S, Tang X L, Qiu Y, Rizvi A, Jadoon A K, Zhang Q, Bolli R
Division of Cardiology, University of Louisville, KY 40292, USA.
Circulation. 1998 Aug 4;98(5):441-9. doi: 10.1161/01.cir.98.5.441.
Despite intense investigation, the effector of the infarct-limiting protection observed during the late phase of ischemic preconditioning (PC) remains unknown. The goal of this study was to test the hypothesis that late PC against myocardial infarction is mediated by the activity of nitric oxide synthase (NOS).
Conscious rabbits underwent a 30-minute coronary occlusion followed by 3 days of reperfusion. In group I (control group, n= 10), infarct size (tetrazolium staining) averaged 56.8+/-5.3% of the risk region, which was decreased to 27.6+/-2.5% (P<0.05) in rabbits preconditioned 24 hours earlier with a sequence of six 4-minute occlusion/4-minute reperfusion cycles (group II, n= 10). When preconditioned rabbits were given the nonselective NOS inhibitor N(omega)-nitro-L-arginine (L-NA, 13 mg/kg i.v. [group III, n=8]) or the selective iNOS inhibitor aminoguanidine (AG, 150 mg/kg SC [group V, n=7]) before the 30-minute occlusion, the protective effect of late PC was completely abrogated; that is, infarct size (59.9+/-4.5% and 65.8+/-3.3%, respectively) was similar to that measured in the control group. Measurements of systolic wall thickening (sonomicrometry) demonstrated that L-NA and AG also abolished the improved recovery of myocardial function effected by late PC in group II. When rabbits were given L-NA or AG without prior PC (group IV [n=8] and group VI [n=6], respectively), infarct size did not differ from that observed in controls (53.8+/-4.3% and 59.8+/-4.3%, respectively), demonstrating that L-NA and AG do not increase the extent of cell death in nonpreconditioned myocardium.
Taken together, these results indicate that in the conscious rabbit, the infarct-sparing effect of the late phase of ischemic PC is mediated by the activity of NOS and suggest that the specific isoform primarily responsible for this cardioprotective phenomenon is iNOS. Thus, NO appears to be a pivotal component of the pathophysiological cascade of late PC.
尽管进行了深入研究，但缺血预处理（PC）后期观察到的梗死面积限制保护作用的效应器仍不清楚。本研究的目的是检验以下假设：晚期PC对心肌梗死的保护作用是由一氧化氮合酶（NOS）的活性介导的。
清醒家兔冠状动脉闭塞30分钟，随后再灌注3天。在第一组（对照组，n = 10）中，梗死面积（四氮唑染色）平均为危险区域的56.8±5.3%，而在24小时前接受6个4分钟闭塞/4分钟再灌注周期预处理的家兔中（第二组，n = 10），梗死面积降至27.6±2.5%（P<0.05）。当预处理的家兔在30分钟闭塞前给予非选择性NOS抑制剂N（ω）-硝基-L-精氨酸（L-NA，13 mg/kg静脉注射[第三组，n = 8]）或选择性诱导型NOS抑制剂氨基胍（AG，150 mg/kg皮下注射[第五组，n = 7]）时，晚期PC的保护作用完全被消除；也就是说，梗死面积（分别为59.9±4.5%和65.8±3.3%）与对照组测得的相似。收缩期壁增厚（超声测量）的测量结果表明，L-NA和AG也消除了第二组中晚期PC对心肌功能改善的恢复作用。当家兔在未进行预处理的情况下给予L-NA或AG时（分别为第四组[n = 8]和第六组[n = 6]），梗死面积与对照组观察到的无差异（分别为53.8±4.3%和59.8±4.3%），表明L-NA和AG不会增加未预处理心肌中的细胞死亡程度。
综上所述，这些结果表明，在清醒家兔中，缺血PC后期的梗死面积减少效应是由NOS的活性介导的，并提示主要负责这种心脏保护现象的特定同工型是诱导型NOS。因此，NO似乎是晚期PC病理生理级联反应的关键组成部分。
