Vaziri N D, Ni Z, Wang X Q, Oveisi F, Zhou X J
Department of Medicine, University of California, Irvine 92868, USA.
Am J Physiol. 1998 Apr;274(4):F642-9. doi: 10.1152/ajprenal.1998.274.4.F642.
The available data on the effect of chronic renal failure (CRF) on nitric oxide (NO) metabolism are limited and contradictory. We studied rats with CRF 6 wk after a five-sixths nephrectomy and compared the results with those in the sham-operated controls, felodipine-treated CRF, and parathyroidectomized (CRF-PTX) animals. CRF was produced by surgical resection of the upper and lower thirds of the left kidney, followed by contralateral nephrectomy. We chose this model, as opposed to that produced by renal artery branch ligation, because the latter causes exuberant hypertension (HTN), which independently affects NO metabolism. The CRF group exhibited a mild HTN coupled with elevated basal platelet cytosolic Ca2+ concentration ([Ca2+]i), blunted hypotensive response to L-arginine, decreased hypertensive response to NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine, and normal hypotensive response to NO donor, sodium nitroprusside. This was associated with a significant reduction in urinary excretion of stable NO metabolites (NOX) and depressed NOS activity, as well as endothelial and inducible NO synthase (eNOS and iNOS, respectively) protein contents of thoracic aorta and the remnant kidney in the CRF animals. Calcium channel blockade and PTX lowered blood pressure, increased urinary NOX, and enhanced vascular NOS activity, as well as eNOS and iNOS protein expressions in the tested tissues. Thus CRF animals exhibited significant reductions in vascular NOS activity and eNOS and iNOS expressions. These abnormalities were reversed by calcium channel blockade and PTX, suggesting the possible causal role of CRF-induced dysregulation of [Ca2+]i.
关于慢性肾衰竭（CRF）对一氧化氮（NO）代谢影响的现有数据有限且相互矛盾。我们研究了在进行五分之六肾切除术后6周的CRF大鼠，并将结果与假手术对照组、非洛地平治疗的CRF大鼠以及甲状旁腺切除（CRF-PTX）动物的结果进行比较。CRF通过手术切除左肾上下三分之一，然后进行对侧肾切除术产生。我们选择这个模型，而不是肾动脉分支结扎产生的模型，因为后者会导致严重高血压（HTN），独立影响NO代谢。CRF组表现出轻度高血压，同时基础血小板胞质Ca2+浓度（[Ca2+]i）升高，对L-精氨酸的降压反应减弱，对NO合酶（NOS）抑制剂NG-单甲基-L-精氨酸的升压反应降低，对NO供体硝普钠的降压反应正常。这与稳定NO代谢产物（NOX）的尿排泄显著减少、NOS活性降低以及CRF动物胸主动脉和残余肾中内皮型和诱导型NO合酶（分别为eNOS和iNOS）蛋白含量降低有关。钙通道阻滞剂和PTX可降低血压，增加尿NOX，并增强受试组织中的血管NOS活性以及eNOS和iNOS蛋白表达。因此，CRF动物的血管NOS活性以及eNOS和iNOS表达显著降低。这些异常通过钙通道阻滞剂和PTX得到逆转，提示CRF诱导的[Ca2+]i调节异常可能起因果作用。
