达芦生坦对大鼠心肌内皮素受体结合的影响及一次给药对肺动脉高压的治疗作用  

Affinity and selectivity of darusentan for rat endothelin receptors and effects of once iv administration of darusentan on hypoxia-induced pulmonary hypertensive in rats

作　　者：夏绘晶[1] 万玫[1] 戴德哉[1] 吉民[2] 郭峰[3] 

机构地区：[1]中国药科大学药理研究室 [2]东南大学化学化工系 [3]中国药科大学新药研究中心

出　　处：《中国临床药理学与治疗学》2006年第3期261-265,共5页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家自然科学基金重点资助课题(№30230170)

摘　　要：目的:研究内皮素受体(ETR)拮抗剂达芦生坦(DR)对大鼠心肌ETR的选择性,及一次给药对肺动脉高压大鼠的治疗作用。方法:放射受体结合方法测定DR对125I-ET与大鼠左室膜ETR竞争结合。对低氧肺动脉高压大鼠静脉注射DR后右室血流动力学的改善作用。结果:DR(0.1μmol.L-1)竞争125I-ET1与心肌ET受体的总结合率降为31.5%±7.7%。抑制125I-ET1与ETAR和ETBR结合的IC50值为1.93±0.21和147±20 nmol.L-1,比值为76。DR输注后20 min明显改善血流动力学。结论:DR是有较高亲和力与选择性的ETAR拮抗剂。急性一次给药对肺动脉高压大鼠血流动力学有明显改善作用。AIM： To investigate the affinity and selectivity of endothelin antagonist darusentan on the ETA and ETB receptor of rat left ventricle and its effect on the hemodynamic parameters in hypoxia-induced pulmonary hypertensive rat. METHODS： Radio receptor binding assay method was used to detemaine the competition binding of darusentan. Pulmonary hypertensive rats were induced by hypoxia. A multiple physiological recorder was used to record the hemodynamic parameters. RESULTS： The competition binding of^125 I-ET1 to ETR at darusentan 0.1μmol.L^-l presence was 31.50% ± 7.7%. The IC50 to suppress ETA and ETB of darusentan was 1.93 ± 0.21 and 147±20 μmol-L^-1. It was 76.16 fold of selectivity for the ETA receptor over the ETB receptor. By 28 d of exposure to hypoxia, rats had already developed significant pulmonary hypertension as estimated by increased right ventricle systolic pressure （RVSP）, right ventricle end diastolic pressure （RVEDP）, right ventricle ＋ dp/dtmax and - dp/dtmax. Once treatment with darusentan by iv injection, pulmonary hypertensive changes were significantly reducad in the right ventricle. CONCLUSION： Darusentan has significantly antagonistic effects on the left ventricle membrane and has high selectivity for ETAR. It effectively ameliorates the hemodynamic parameters in hypoxia-induced pulmonary hypertensive rats.

关 键 词：内皮素受体拮抗剂 内皮素受体 放射受体分析 肺动脉高压 低氧 血流动力学 

分 类 号：R965.2[医药卫生—药理学]