Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis.
Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis.
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肝硬化大鼠的神经元一氧化氮合酶和全身血管舒张。
DOI：
10.1152/ajprenal.2000.279.6.f1110
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Schrier,RW
中科院分区：
文献类型：
--
作者：
Xu,L;Carter,EP;Ohara,M;Martin,PY;Rogachev,B;Morris,K;Cadnapaphornchai,M;Knotek,M;Schrier,RW
肝硬化通常与由低血压、低全身血管阻力（SVR）和高心输出量组成的高动力循环相关。我们最近报道，用硝基-L-精氨酸甲酯非特异性抑制一氧化氮合酶（NOS）逆转四氯化碳（CCl_4）诱导的晚期肝硬化大鼠的高动力循环。虽然内皮型一氧化氮合酶（eNOS）在肝硬化中有重要作用，但神经型一氧化氮合酶（nNOS）的作用尚未研究。本研究旨在探讨nNOS在肝硬化过程中的作用。具体而言，生理，生化和分子的方法来评估nNOS的贡献，在四氯化碳诱导的腹水大鼠腹水相关的高动力循环。肝硬化动物的水和钠潴留显著增加。与对照组相比，主动脉nNOS蛋白表达和cGMP浓度均显著升高。用特异性nNOS抑制剂7-硝基吲唑（7-NI）治疗强直性脊柱炎大鼠7天，使低SVR和平均动脉压恢复正常，心脏指数升高，并逆转了正钠平衡。增加血浆精氨酸加压素的浓度在阿尔茨海默病的动物也与7-NI抑制减少水潴留。循环变化与主动脉nNOS表达和cGMP的减少有关。然而，7-NI治疗并不能恢复糖尿病大鼠的肾功能（肌酐清除率：糖尿病大鼠为0.76 ± 0.03 ml·min-1·100 g体重-1，糖尿病大鼠+7-NI治疗为0.79 ± 0.05 ml·min-1·100 g体重-1; PNS）。总之，这些结果表明，nNOS衍生的NO有助于肝硬化的高动力循环和液体潴留的发展。
Cirrhosis is typically associated with a hyperdynamic circulation consisting of low blood pressure, low systemic vascular resistance (SVR), and high cardiac output. We have recently reported that nonspecific inhibition of nitric oxide synthase (NOS) with nitro-l-arginine methyl ester reverses the hyperdynamic circulation in rats with advanced liver cirrhosis induced by carbon tetrachloride (CCl4). Although an important role for endothelial NOS (eNOS) is documented in cirrhosis, the role of neuronal NOS (nNOS) has not been investigated. The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis. Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl4-induced cirrhotic rats with ascites. Cirrhotic animals had a significant increase in water and sodium retention. In the aorta from cirrhotic animals, both nNOS protein expression and cGMP concentration were significantly elevated compared with control. Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance. Increased plasma arginine vasopressin concentrations in the cirrhotic animals were also repressed with 7-NI in association with diminished water retention. The circulatory changes were associated with a reduction in aortic nNOS expression and cGMP. However, 7-NI treatment did not restore renal function in cirrhotic rats (creatinine clearance: 0.76 ± 0.03 ml · min−1· 100 g body wt−1in cirrhotic rats vs. 0.79 ± 0.05 ml · min−1· 100 g body wt−1in cirrhotic rats+7-NI;PNS.). Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis.