盐酸埃他卡林对内皮素-1 诱导的大鼠肺动脉高压的影响

中国临床药理学与治疗学 ›› 2005, Vol. 10 ›› Issue (1): 9-14.

盐酸埃他卡林对内皮素-1 诱导的大鼠肺动脉高压的影响

王虹^1,2, 解卫平^1,2, 汪海³, 胡刚¹

¹南京医科大学药理学系, ²第一附属医院呼吸内科, 南京 210029, 江苏;
³军事医学科学院药物毒物研究所, 北京 100850

收稿日期:2004-12-07 修回日期:2005-01-05 出版日期:2005-01-26 发布日期:2020-11-19
通讯作者: 胡刚, 男, 博士, 教授, 博士生导师, 主要从事分子药理学与临床药理学研究。Tel:025-86663169 E-mail:ghu@njmu.edu.cn
作者简介:王虹, 女, 博士, 主任医师, 教授, 从事肺动脉高压的基础和临床研究。
基金资助:
国家创新药物基础研究重大项目基金(No969010101);国家自然科学基金(No39970846);江苏省科委社会发展基金(NoBJ2000051);江苏省教育厅基金(No00KJB320009)

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

WANG Hong^1,2, XIE Wei-ping^1,2, WANG Hai³, HU Gang¹

¹Department of Pharmacology, ²Department of Pulmonology, the First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China;
³Institute of Pharmacology and Toxicology, Molitary Medicine and Sciene Academic, Beijing 100850, China

Received:2004-12-07 Revised:2005-01-05 Online:2005-01-26 Published:2020-11-19

摘要/Abstract

摘要： 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、20、30、60 min 的平均肺动脉压;观察注射ET-1 前或注射后2 min 给予IPT 对肺动脉压的影响。结果: 在0.05～50 nmol·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10.48±1.52 nmol·L^-1, b±Sb 为0.82±0.085, 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5.84 nmol·L^-1。预先注入IPT(1.0 和0.5 mg·kg^-1)可以拮抗ET-1 诱导的肺动脉高压;预先注入选择性K_ATP拮抗剂格列本脲20 mg·kg^-1则可阻断IPT 的作用。给予ET-1 后2 min 经肺动脉注入IPT(1.0 mg·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K_ATP 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物。

关键词: 肺动脉高压, ATP 敏感性钾通道, 内皮素-1, 盐酸埃他卡林, 大鼠

Abstract: 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^-1antagonized vasoconstriction induced by ET-1 in a concentration-dependent manner.The IC₅₀ 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^-1could prevent the pulmonary hypertension induced by ET-1.The prevention of ET-1-induced pulmonary hypertension afforded by IPT 1.0mg·kg^-1was abolished by pretreatment of rats with the K_ATP channel inhibitors, glibenclimide (Gli).IPT of 1.0 mg·kg^-1blocked pulmonary hypertension induced by ET-1 10, 20 and 30 minutes after ET-1 infusion.But IPT 0.5 mg·kg^-1had no effect on pulmonary hypertension induced by ET-1. IPT 1.0 or 0.5 mg·kg^-1which was administered as a bolus infusion into pulmonary artery had no effect on normal pulmonary artery pressure.CONCLUSION: IPT of 1.0 mg·kg^-1can 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.

Key words: pulmonary hypertension, ATP-sensitive potassium channel, endothelin-1, iptakalim hydrochloride

中图分类号:

R972

王虹, 解卫平, 汪海, 胡刚. 盐酸埃他卡林对内皮素-1 诱导的大鼠肺动脉高压的影响[J]. 中国临床药理学与治疗学, 2005, 10(1): 9-14.

WANG Hong, XIE Wei-ping, WANG Hai, HU Gang. Effects of iptakalim on endothelin-1-induced pulmonary hypertension in rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(1): 9-14.

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