EFFECT OF NALOXONE ON RENAL FUNCTIONS IN LIVER CIRRHOSIS

肾功能异常(肾血流动力学和水分受损 电解质排泄)常见于肝硬变患者。 具有抗利尿特性的内源性阿片类药物的循环水平可能 在肝硬变中增加，阿片类拮抗剂纳洛酮 增加内生肌酐清除和水和电解质排泄 水负荷的肝硬变和腹水患者。问题1：是否存在 阿片类拮抗剂纳洛酮对慢性阻塞性肺疾病患者的利尿作用 与肾脏血流动力学增加相关的肝硬变和腹水 (肾血浆流量和肾小球滤过率)或循环水平 已知的影响肾血流动力学或肾小管功能的激素？你能不能 长期输注纳洛酮会导致持续性的肾脏影响吗？问题 2：目前在肝硬变患者中使用的利尿剂是否有效？ 同时服用纳洛酮能提高疗效吗？问题3：是 肝硬变患者内源性阿片系统激活？ 酒精性肝硬变和腹水患者基本正常 (肌酐清除量大于或等于70毫升/分钟)或降低 (低于70毫升/分钟)肾小球滤过率将经历急性 (5H)和慢性(48h)纳洛酮输注研究 对肾脏血流动力学、水和电解质排泄的影响，以及 已知的影响肾功能的激素。衡量标准将包括 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、心房素 利钠肽、胰升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类代谢物。电浆 内源性阿片类药物(β-内啡肽、脑啡肽和强啡肽)将 由高效液相色谱/放射免疫法测定，以确定哪些阿片类药物在 肝硬变患者和循环水平是否与基础值相关 肾功能参数或肾脏的大小 纳洛酮的血流动力学/利尿剂反应。我们预计纳洛酮将 增加肾小球滤过率，从而导致利尿；更多 重要的是，纳洛酮应该会显著增强 目前用于这种情况的利尿剂(速尿和速尿 螺内酯)。因为目前还没有治疗药物 可预测地改善肝硬变患者的肾血流动力学 腹水，我们的研究结果不仅应该提供关于 内源性阿片类药物在肝病中的作用，但可能被证明 在临床上非常有用。

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.