Cottart C H, Do L, Blanc M C, Vaubourdolle M, Descamps G, Durand D, Galen F X, Clot J P
Department of Endocrinology, UFR des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France.
Hepatology. 1999 Mar;29(3):809-13. doi: 10.1002/hep.510290317.
The aim of this study was to evaluate the protective or deleterious effects of endogenous nitric oxide (NO) on liver cells during hepatic ischemia-reperfusion (IR) in the rat. Injury to hepatocytes and endothelial cells was evaluated by determining cytolysis-marker activity in plasma (alanine transaminase [ALT]; aspartate transaminase [AST]) and plasma hyaluronic acid (HA) concentration. Clamping the hepatic pedicle for 45 minutes caused a significant increase in plasma AST and ALT activity after 30 minutes of reperfusion, which reached a maximum (+270% and +740%, respectively) after 6 hours of reperfusion. Plasma HA concentration was significantly higher (+130%) only after 6 hours of reperfusion. Administration of a nonselective NO synthase (NOS) inhibitor, Nomega-nitro-L-arginine (L-NNA; 10 mg/kg iv), 30 minutes before IR, caused marked aggravation of postischemic liver injury, as shown by plasma ALT and AST activity and HA concentration. This deleterious effect was partially prevented by the simultaneous injection of L-arginine, the endogenous NO precursor (100 mg/kg iv). Interestingly, L-arginine alone limited postischemic damage (AST, -25%; ALT, -45%; HA, -21% vs. untreated IR rats at 6 hours reperfusion). Pretreatment with the Guanosine 3':5'-cyclic monophosphate-independent vasodilator, prazosin, partially reversed L-NNA effects, but it did not protect untreated IR animals. Pretreatment with aminoguanidine, a selective inhibitor of inducible NOS, did not aggravate hepatic IR injury. Thus, endogenous NO, probably produced by an early and transient activation of a constitutive NOS, protects both hepatocytes and endothelial cells against liver ischemia-reperfusion injury, and this effect is not entirely a result of vasorelaxation.
本研究的目的是评估内源性一氧化氮（NO）在大鼠肝脏缺血再灌注（IR）过程中对肝细胞的保护或有害作用。通过测定血浆中的细胞溶解标志物活性（丙氨酸转氨酶[ALT]；天冬氨酸转氨酶[AST]）和血浆透明质酸（HA）浓度来评估肝细胞和内皮细胞的损伤。肝蒂夹闭45分钟后，再灌注30分钟时血浆AST和ALT活性显著升高，再灌注6小时后达到最大值（分别为+270%和+740%）。仅在再灌注6小时后，血浆HA浓度显著升高（+130%）。在IR前30分钟给予非选择性一氧化氮合酶（NOS）抑制剂Nω-硝基-L-精氨酸（L-NNA；10 mg/kg静脉注射），可导致缺血后肝损伤明显加重，这可通过血浆ALT和AST活性以及HA浓度表现出来。同时注射内源性NO前体L-精氨酸（100 mg/kg静脉注射）可部分预防这种有害作用。有趣的是，单独使用L-精氨酸可减轻缺血后损伤（再灌注6小时时，与未治疗的IR大鼠相比，AST降低-25%；ALT降低-45%；HA降低-21%）。用不依赖鸟苷3':5'-环磷酸的血管舒张剂哌唑嗪预处理可部分逆转L-NNA的作用，但它并不能保护未治疗的IR动物。用诱导型NOS的选择性抑制剂氨基胍预处理并不会加重肝脏IR损伤。因此，内源性NO可能由组成型NOS的早期短暂激活产生，可保护肝细胞和内皮细胞免受肝脏缺血再灌注损伤，并且这种作用并不完全是血管舒张的结果。
