盐酸埃他卡林对内皮素1诱导的大鼠肺动脉高压的影响

Effects of iptakalim on endothelin-1-induced pulmonary hypertension in rats

目的 :研究埃他卡林 (iptakalim ,IPT)对内皮素 1(ET 1)诱导的大鼠肺动脉环收缩、肺动脉高压的影响及其机制。方法 :正常SD大鼠肺动脉环建立ET 1的浓度反应曲线 ,研究IPT累积给药的舒张血管效应 ;通过微型导管直接向麻醉大鼠肺动脉注射药物 ,四道生理记录仪记录大鼠肺动脉平均压(mPAP)、平均动脉压 (mAP)和心率 (HR) ;直接向肺动脉注射ET 1,测定注射后 5、10、2 0、30、6 0min的平均肺动脉压 ;观察注射ET 1前或注射后 2min给予IPT对肺动脉压的影响。结果 :在 0 .0 5～5 0nmol·L-1浓度范围内 ,ET 1呈浓度依赖性地引起肺动脉环收缩 ,其EC50 ±L95为 10 .4 8±1.5 2nmol·L-1,b±Sb 为 0 .82± 0 .0 85 ,r =0 .97。在10 -13 ～ 10 -3 nmol·L-1浓度时 ,IPT呈浓度依赖地拮抗ET 1诱导的肺动脉环收缩 ,其IC50 为5 .84nmol·L-1。预先注入IPT(1.0和 0 .5mg·kg-1)可以拮抗ET 1诱导的肺动脉高压 ;预先注入选择性KATP拮抗剂格列本脲 2 0mg·kg-1则可阻断IPT的作用。给予ET 1后 2min经肺动脉注入IPT(1.0mg·kg-1)可阻断ET 1诱导的肺动脉压升高。结论 :IPT可显著拮抗或逆转ET 1诱导的肺动脉高压 ,其机制在于开放KATP通道 ,预先给予IPT的效果优于肺动脉高压形成后给药 ,IPT是一个富有潜力的治疗肺动脉高压的候选药?

AIM : To investigate the effects of iptakalim hydrochloride (IPT) on endothelin 1 (ET 1) induced pulmonary hypertension in rats. METHODS : The effects of IPT administered by cumulative method on vasoconstriction mediated by ET 1 were studied with rings of pulmonary arteries isolated from normal rats. The rat model of pulmonary hypertension was prepared by injecting ET 1 through pulmonary artery. The mean pulmonary arterial pressure (mPAP), heart rate (HR), systemic blood pressure were monitored by polygraph. RESULTS: In vitro studies, IPT at the concentration of 0.05 to 50 nmol·L -1 antagonized vasoconstriction induced by ET 1 in a concentration dependent manner. The IC 50 value for dilating PA rings preconstricted with ET 1 was 5.84 nmol·L -1 . In vivo studies, ET 1 induced a significant increase in mPAP from 21.37 ± 2.64 mmHg to 26.23 ± 3.94 mmHg. Pulmonary artery pressure recovered 60 minutes after ET 1 infusion. Both IPT 1.0 and 0.5 mg·kg -1 could prevent the pulmonary hypertension induced by ET 1. The prevention of ET 1 induced pulmonary hypertension afforded by IPT 1.0 mg·kg -1 was abolished by pretreatment of rats with the K ATP channel inhibitors, glibenclimide (Gli). IPT of 1.0 mg·kg -1 blocked pulmonary hypertension induced by ET 1 10, 20 and 30 minutes after ET 1 infusion. But IPT 0.5 mg·kg -1 had no effect on pulmonary hypertension induced by ET 1. IPT 1.0 or 0.5 mg·kg -1 which was administered as a bolus infusion into pulmonary artery had no effect on normal pulmonary artery pressure. CONCLUSION : IPT of 1.0 mg·kg -1 can significantly treat and prevent the pulmonary hypertension induced by ET 1 through activating K ATP channel without affecting normal pulmonary artery pressure. It is a promising candidate for the treatment of pulmonary hypertension.