EFFECT OF NALOXONE ON RENAL FUNCTIONS IN LIVER CIRRHOSIS

肾功能异常（肾血流动力学和水功能受损， 电解质排泄）在肝硬化患者中常见。 具有抗利尿特性的内源性阿片类物质的循环水平可能 在肝硬化中增加，阿片类拮抗剂纳洛酮 增加肌酐清除率和水和电解质排泄， 肝硬化和腹水的水负荷患者。问题1： 阿片受体拮抗剂纳洛酮的利尿作用 肝硬化和腹水与肾血流动力学增加相关 （肾血浆流量和肾小球滤过率）或循环水平 已知影响肾血流动力学或肾小管功能的激素？能 长期输注纳洛酮会导致持续的肾脏效应吗？ 问题 2：目前在糖尿病患者中使用的利尿剂的效果是否可以 同时服用纳洛酮会增强吗 问题3： 内源性阿片系统激活的阿尔茨海默病患者？ 酒精性肝硬化和腹水患者， （肌酐清除率大于或等于70 mL/min）或降低 (less 70 mL/min）肾小球滤过率将经历急性 (5h)和慢性（48小时）纳洛酮输注研究，以确定其 对肾血流动力学、水和电解质排泄的影响，以及 影响肾功能的激素 测量将包括 有效肾血浆流量和肾小球滤过率（菊粉，PAH， 和放射性同位素方法），水和溶质排泄参数，血浆 肾素、血管紧张素II、醛固酮、儿茶酚胺、加压素、心房 利钠肽、胰高血糖素和胰岛素样生长因子（IGF-1）， 尿血管扩张剂前列腺素和血栓素代谢物。 血浆 内源性阿片类物质（β-内啡肽，脑啡肽和强啡肽）将被 通过HPLC/RIA测定，以确定哪些阿片类药物在 血液循环水平是否与基础胰岛素水平相关 肾功能参数或肾功能的大小 血液动力学/利尿反应。 我们认为纳洛酮 增加肾小球滤过率，从而导致利尿;更多 重要的是，纳洛酮应显著增强 目前用于这种情况的利尿剂（呋塞米和 螺内酯）。 由于目前没有治疗剂 可预测地改善肝硬化患者的肾血流动力学， 腹水，我们的研究结果不仅应该提供基本的信息， 内源性阿片类药物在肝脏疾病中的作用，但可能被证明是 临床上非常有用。

Renal functional abnormalities (impaired renal hemodynamics and water and electrolyte excretion) are commonly seen in patients with liver cirrhosis. Circulating levels of endogenous opioids with antidiuretic properties may be increased in liver cirrhosis, and the opioid antagonist naloxone increases creatinine clearance and water and electrolyte excretion in water-loaded patients with cirrhosis and ascites. Question 1: Are the diuretic effects of the opioid antagonist naloxone in patients with cirrhosis and ascites associated with an increase in renal hemodynamics (renal plasma flow and glomerular filtration rate) or circulating levels of hormones known to affect renal hemodynamics or tubular functions? Can a chronic infusion of naloxone result in sustained renal effects? Question 2: Can the effects of diuretics currently utilized in cirrhotic patients be enhanced by simultaneous administration of naloxone? Question 3: Are endogenous opioid systems activated in cirrhotic patients? Patients with alcoholic cirrhosis and ascites with essentially normal (creatinine clearance greater than or equal to 70 mL/min) or depressed (less than 70 mL/min) glomerular filtration rate will undergo both acute (5h) and chronic (48h) naloxone infusion studies in order to determine its effects on renal hemodynamics, water and electrolyte excretion, and hormones known to affect renal functions. Measurements will include effective renal plasma flow and glomerular filtration rate (inulin, PAH, and radioisotopic methods), water and solute excretion parameters, plasma renin, angiotensin II, aldosterone, catecholamines, vasopressin, atrial natriuretic peptide, glucagon, and insulin-like growth factor (IGF-1), urinary vasodilator prostaglandin and thromboxane metabolites. Plasma endogenous opioids (beta-endorphin, enkephalins, and dynorphin) will be determined by HPLC/RIA in order to determine which opioids are increased in cirrhotic patients and whether the circulating level correlates with basal renal functional parameters or the magnitude of the renal hemodynamic/diuretic response to naloxone. We expect that naloxone will increase glomerular filtration rate, thus resulting in diuresis; more importantly, naloxone should markedly potentiate the effect of currently-used diuretics for this condition (furosemide and spironolactone). As there are currently no therapeutic agents which predictably improve renal hemodynamics in patients with liver cirrhosis and ascites, our study findings should not only provide basic information on the role of endogenous opioids in liver disease but might prove to be clinically very useful.