Kupatt C, Habazettl H, Zahler S, Weber C, Becker B F, Messmer K, Gerlach E
Department of Physiology, Ludwig-Maximilians-University, Munich, Germany.
Cardiovasc Res. 1997 Dec;36(3):386-95. doi: 10.1016/s0008-6363(97)00191-0.
Polymorphonuclear leukocytes (PMN), retained in the microvascular bed, can contribute to postischemic myocardial reperfusion injury. Since a beneficial effect of ACE-inhibition on reperfusion injury has been reported, we investigated the impact of cilazaprilat on PMN dependent reperfusion injury in isolated guinea pig hearts.
Hearts (n = 5 per group) were subjected to 15 min of ischemia. Immediately thereafter, a bolus of PMN was injected into the coronary system. External heart work (EHW) and total cardiac nitric oxide release were measured. For microscopic evaluation, hearts received rhodamine 6G labelled PMN after ischemia, were arrested 5 min later and further perfused with FITC dextran (0.1%). Localization of retained PMN was assessed by fluorescence microscopy. Leukocyte activation was studied by FACS analysis of the adhesion molecule CD11b before and after coronary passage of the PMN. The ACE-inhibitor cilazaprilat (Cila, 2 microM) and the NO-synthase inhibitor nitro-L-arginine (NOLAG, 10 microM) were used to modulate nitric oxide formation of the heart.
Postischemic EHW recovered to 67 +/- 5% (controls) and 64 +/- 6% (Cila) of the preischemic value. Addition of PMN severely depressed recovery of EHW (39 +/- 2%) and NO release (39 +/- 6% of the preischemic value). Simultaneously, ischemia led to a substantial increase in postcapillary PMN adhesion (from 21 +/- 5 to 172 +/- 27 PMN/mm2 surface) and CD11b-expression of the recovered PMN (3-fold). Cila attenuated postischemic PMN adhesion (83 +/- 52 PMN/mm2) and activation of PMN, whereas it improved recovery of work performance (64 +/- 4%) and NO release (65 +/- 4%) in the presence of PMN. Conversely, NOLAG increased PMN adhesion (284 +/- 40 PMN/mm2) and myocardial injury. We conclude that ACE-inhibition prevents leukocyte dependent reperfusion injury mainly by inhibition of postcapillary leukocyte adhesion. The effect may be mediated by NO, given the proadhesive effect of NOLAG.
滞留于微血管床的多形核白细胞（PMN）可导致缺血后心肌再灌注损伤。由于已有报道称血管紧张素转换酶（ACE）抑制对再灌注损伤具有有益作用，我们研究了西拉普利拉对离体豚鼠心脏中PMN依赖性再灌注损伤的影响。
心脏（每组n = 5）经历15分钟的缺血。此后立即将一剂PMN注入冠状动脉系统。测量心脏外部做功（EHW）和总心脏一氧化氮释放量。为进行显微镜评估，心脏在缺血后接受罗丹明6G标记的PMN，5分钟后停跳，并进一步用异硫氰酸荧光素葡聚糖（0.1%）灌注。通过荧光显微镜评估滞留PMN的定位。通过对PMN冠状动脉灌注前后粘附分子CD11b的流式细胞术分析研究白细胞活化情况。使用ACE抑制剂西拉普利拉（Cila，2微摩尔）和一氧化氮合酶抑制剂硝基-L-精氨酸（NOLAG，10微摩尔）来调节心脏的一氧化氮生成。
缺血后EHW恢复至缺血前值的67±5%（对照组）和64±6%（Cila组）。添加PMN严重抑制了EHW的恢复（39±2%）和一氧化氮释放（缺血前值的39±6%）。同时，缺血导致毛细血管后PMN粘附显著增加（从21±5至172±27个PMN/mm²表面）以及恢复的PMN的CD11b表达增加（3倍）。Cila减轻了缺血后PMN的粘附（83±52个PMN/mm²）和PMN的活化，而在存在PMN的情况下改善了做功性能的恢复（64±4%）和一氧化氮释放（65±4%）。相反，NOLAG增加了PMN的粘附（284±40个PMN/mm²）和心肌损伤。我们得出结论，ACE抑制主要通过抑制毛细血管后白细胞粘附来预防白细胞依赖性再灌注损伤。鉴于NOLAG的促粘附作用，该效应可能由一氧化氮介导。
