Sansoè G, Silvano S, Mengozzi G, Smedile A, Todros L, Baronio M, Bonardi L, Rizzetto M
Gastroenterology Unit, Gradenigo Hospital, Torino, Italy.
Am J Gastroenterol. 2002 Sep;97(9):2383-90. doi: 10.1111/j.1572-0241.2002.05992.x.
Several studies in human cirrhosis have demonstrated increased nitric oxide (NO) production. In experimental animals, intracerebroventricular administration of NO donors causes a marked depression of the endogenous dopaminergic activity, a function known to be physiologically recruited and exerting a natriuretic function in patients with compensated cirrhosis. The aim of this study is to evaluate the interaction between the systemic plasma levels of NO, the endogenous dopaminergic activity and the main parameters of renal function in patients with liver cirrhosis of differing degrees of severity.
A total of 21 patients (11 with preascitic and 10 with nonazotemic diuretic-free ascitic cirrhosis) and 10 healthy control subjects underwent the following tests: a) basal plasma renin activity (PRA) and aldosterone levels; b) renal clearances of sodium, potassium, inulin, para-minohippurate and lithium (the latter being a measure of the fluid delivery to the distal nephron); c) NO systemic plasma levels measured through paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes; d) endogenous dopaminergic activity, evaluated by means of the incremental prolactin and aldosterone plasma levels after dopaminergic blockade with i.v. metoclopramide.
NO plasma values and endogenous dopaminergic activity, although significantly increased with respect to healthy controls, were not different in the two groups of patients. The plasma NO/PRA ratio was significantly higher in the group of compensated patients with respect to ascitic cirrhotics (respectively, 18.3 +/- 11.8 vs 3.5 +/- 2.6 A.U./ng/ml/h, p < 0.001). Compared with compensated cirrhotics, patients with ascites showed significantly lower values of glomerular filtration rate (GFR) and renal plasma flow (RPF). Interestingly, GFR values were substantially the same in the ascitic patients and the control subjects. Compensated patients displayed a significant positive correlation between metoclopramide-induced incremental aldosterone plasma levels (i.e., endogenous dopaminergic tone) and fractional excretion of sodium (r = 0.58; p < 0.05). In the group of compensated patients, NO levels correlated inversely with creatinine plasma concentrations (r = -0.85; p < 0.001) and directly with inulin clearance (r = 0.65; p < 0.05).
These data show that, at least in compensated cirrhotic patients, the stimulation of systemic NO production and the increased dopaminergic function may be mechanisms preventing renal perfusion, GFR, and fractional excretion of sodium from precocious reductions.
多项针对人类肝硬化的研究表明一氧化氮（NO）生成增加。在实验动物中，脑室内给予NO供体可导致内源性多巴胺能活性显著降低，而这一功能在代偿期肝硬化患者中可被生理性激活并发挥利钠作用。本研究旨在评估不同严重程度肝硬化患者的全身血浆NO水平、内源性多巴胺能活性与肾功能主要参数之间的相互作用。
共有21例患者（11例为腹水前期患者，10例为无氮质血症且未使用利尿剂的腹水型肝硬化患者）和10名健康对照者接受了以下检查：a）基础血浆肾素活性（PRA）和醛固酮水平；b）钠、钾、菊粉、对氨基马尿酸和锂的肾清除率（后者用于衡量远端肾单位的液体输送量）；c）通过顺磁共振波谱法测量作为亚硝基血红蛋白复合物的全身血浆NO水平；d）内源性多巴胺能活性，通过静脉注射甲氧氯普胺进行多巴胺能阻断后，检测催乳素和醛固酮血浆水平的增量来评估。
尽管与健康对照者相比，两组患者的血浆NO值和内源性多巴胺能活性均显著升高，但两组患者之间并无差异。代偿期患者组的血浆NO/PRA比值显著高于腹水型肝硬化患者组（分别为18.3±11.8与3.5±2.6 A.U./ng/ml/h，p<0.001）。与代偿期肝硬化患者相比，腹水患者的肾小球滤过率（GFR）和肾血浆流量（RPF）值显著更低。有趣的是，腹水患者和对照者的GFR值基本相同。代偿期患者中，甲氧氯普胺诱导的醛固酮血浆水平增量（即内源性多巴胺能张力）与钠分数排泄之间存在显著正相关（r = 0.58；p<0.05）。在代偿期患者组中，NO水平与血浆肌酐浓度呈负相关（r = -0.85；p<0.001），与菊粉清除率呈正相关（r = 0.65；p<0.05）。
这些数据表明，至少在代偿期肝硬化患者中，全身NO生成的刺激和多巴胺能功能的增强可能是防止肾灌注、GFR和钠分数排泄过早降低的机制。
