Weigert A L, Martin P Y, Niederberger M, Higa E M, McMurtry I F, Gines P, Schrier R W
Division of Renal Diseases, University of Colorado, Denver, USA.
Hepatology. 1995 Dec;22(6):1856-62.
The present experiments were designed to test if induction of nitric oxide synthase (NOS) plays a role in the systemic vasodilation observed in hepatic cirrhosis. Because endotoxin levels are elevated in cirrhosis, and endotoxin stimulates inducible nitric oxide synthase (iNOS) expression in several cell lines, aortas of carbon tetrachloride-induced cirrhotic rats with ascites were evaluated for iNOS expression. Endotoxin-treated rats were studied as positive controls. Phenylephrine contraction was decreased in aortic rings with endothelium from both endotoxin-treated and cirrhotic rats as compared with controls. However, after endothelium denudation, the reduced contractility persisted in endotoxin-treated rats but disappeared in cirrhotic rats. L-Nitro-arginine-methylester (L-NAME), a nonselective inhibitor of NOS, potentiated the phenylephrine contraction of aortic rings with and without endothelium from endotoxin-treated rats but only rings with endothelium from cirrhotic rats. Moreover, aminoguanidine (AG), a preferential inhibitor of iNOS, did not affect phenylephrine contraction of rings with or without endothelium from cirrhotic rats but reversed the blunted response in endotoxin-treated rats. Northern analysis detected iNOS RNA (mRNA) expression in aortas of endotoxin-treated rats but did not detect it from cirrhotic rats. In summary, although several previous studies provide evidence for in vivo overproduction of nitric oxide in cirrhosis, the present results do not support iNOS induction as the source of nitric oxide in aortas of cirrhotic rats. Rather, because the aortic vascular hyporesponsiveness in cirrhosis is endothelium-dependent, overexpression or overstimulation of the endothelial constitutive isoform of NOS appears to be involved.
本实验旨在检验一氧化氮合酶（NOS）的诱导是否在肝硬化时观察到的全身血管舒张中起作用。由于肝硬化时内毒素水平升高，且内毒素可刺激多种细胞系中诱导型一氧化氮合酶（iNOS）的表达，因此对四氯化碳诱导的有腹水的肝硬化大鼠的主动脉进行了iNOS表达评估。以内毒素处理的大鼠作为阳性对照。与对照组相比，内毒素处理大鼠和肝硬化大鼠的带内皮主动脉环中去氧肾上腺素收缩反应减弱。然而，内皮剥脱后，内毒素处理大鼠的收缩性降低持续存在，而肝硬化大鼠的收缩性降低消失。L-硝基-精氨酸甲酯（L-NAME）是一种非选择性NOS抑制剂，可增强内毒素处理大鼠带内皮和不带内皮主动脉环中去氧肾上腺素的收缩反应，但仅增强肝硬化大鼠带内皮主动脉环的收缩反应。此外，氨基胍（AG）是一种iNOS的选择性抑制剂，不影响肝硬化大鼠带内皮或不带内皮主动脉环中去氧肾上腺素的收缩反应，但可逆转内毒素处理大鼠的反应减弱。Northern分析在内毒素处理大鼠的主动脉中检测到iNOS RNA（mRNA）表达，但在肝硬化大鼠中未检测到。总之，尽管先前的一些研究为肝硬化时体内一氧化氮的过量产生提供了证据，但目前的结果不支持iNOS诱导是肝硬化大鼠主动脉中一氧化氮的来源。相反，由于肝硬化时主动脉血管反应性降低是内皮依赖性的，因此似乎涉及内皮组成型NOS同工型的过度表达或过度刺激。
