新型内皮素受体拮抗剂CPU0214与正常大鼠心肌ET受体结合特点及对清醒DOCA-盐型高血压大鼠的降压作用

目的　研究新型内皮素受体拮抗剂CPU0 2 1 4与正常大鼠心肌内皮素 (ET)受体结合特点 ,对血管收缩的拮抗作用及对高血压大鼠血压的降低作用。方法　采用放射配体竞争抑制结合法和ET 1引起的胸主动脉环收缩法分别研究CPU0 2 1 4与正常大鼠心肌ET受体结合的特性和对血管收缩功能的拮抗作用 ;采用放射配体结合法观察注射醋酸脱氧皮质酮 (DO CA)和饮用盐水造成的高血压模型大鼠的心肌ET受体的改变及其股动脉平均动脉压的变化 ,研究CPU0 2 1 4的降压作用。结果　CPU0 2 1 4在正常心肌膜上竞争性结合1 2 5I ET1 ,其IC50 为1 6nmol·L-1 ;抑制ET 1所致胸主动脉环收缩。DOCA 盐型高血压大鼠表现内皮素受体的Bmax值和Kd 值升高 ;CPU0 2 1 4使清醒高血压大鼠的平均动脉压明显降低 ,在 6 0～ 90min时最为明显。结论　CPU0 2 1 4在正常大鼠竞争结合内皮素受体、拮抗血管收缩 ,在内皮素异常高血压大鼠可降低其血压 ,表明CPU0 2 1 4对治疗高血压有良好的研究价值

Antagonistic effects of new endothelin antagonist CPU0214 on cardiac endothelin receptor binding and vascular activity and its reduction on mean arterial pressure in conscious DOCA-salt hypertensive rats

AIM To determine the antagonistic activities of new endothelin receptor antagonist CPU0214 on the left ventricle membranes and the aorta ring contraction in normal rat and its reduction effect on the mean arterial pressure in conscious DOCA salt hypertensive rats. METHODS Left ventricle membranes of normal rat hearts achieved for competition binding assay was used to investigate the antagonistic effects of CPU0214. Aorta ring contraction induced by ET 1 in normal rat was used to investigate the antagonistic activity of CPU0214. DOCA salt hypertensive rats were induced by injection of deoxycorticosterone acetate (DOCA, sc) following with 1% NaCl as drinking for 4 wk. A multiple physiological recorder was used to record the mean arterial pressure of femoral artery. The endothelin receptor change in the left ventricle membranes of DOCA salt hypertensive rat was measured by binding assays. Intraperitoneal injection of CPU0214 was used to investigate its effect on reduction of mean arterial pressure. RESULTS In the left ventricle the IC 50 of endothelin receptor antagonist CPU0214 is 16 nmol·L -1 and CPU0214 (10 μmol·L -1 ) inhibited the ET 1 induced isolated aorta rings contraction in normal rats. Mean arterial pressure as well as B max and K d of left ventricle were increased significantly in DOCA salt hypertensive rat. CPU0214 (60 mg·kg -1 ip) significantly reduced the mean arterial pressure of conscious DOCA salt hypertensive rats especially during 60～90 min after administration. CONCLUSIONS CPU0214 has significantly antagonistic effects on the left ventricle membrane and the isolated aorta ring contraction in normal rat, which is verified by CPU0214 as a strong endothelin receptor antagonist. Furthermore its effect on the mean blood pressure reduction in conscious DOCA salt hypertensive rats, which is manifested as an abnormal endothelin system, shows its prosperity of drug development value as a new endothelin receptor antagonist.