新型ATP敏感性钾通道开放剂Iptakalim对慢性缺氧大鼠肺内动脉平滑肌细胞钾电流的影响

Effects of iptakalim, a novel KATP opener, on potassium currents in intra-pulmonary artery smooth muscles derived from chronic hypoxic rats

目的探讨慢性缺氧对大鼠肺内动脉平滑肌细胞外向性钾电流的影响,及新型ATP敏感性钾（KATP）通道开放剂Iptakalim对此时钾电流的作用。方法SD雄性大鼠28只随机分成正常组、缺氧组[O2（10±0.5）%]、低剂量治疗组（每日缺氧前30min Iptakalim0.75mg·kg^-1灌胃）、高剂量治疗组（每日缺氧前30min Iptakalim1.5mg·kg^-1灌胃）,将缺氧组和已灌胃的大鼠放入常压缺氧舱制作动物模型。4周后,急性分离大鼠动脉平滑肌细胞,用膜片钳全细胞记录技术记录细胞外向性钾电流;通过浴槽内给药,观察Iptakalim对钾电流的影响。结果Iptakalim0.1,1,10,100μmol/L呈浓度依赖性增加正常大鼠肺内动脉平滑肌外向钾电流,格列本脲30μmol/L可拮抗Iptakalim10μmol/L对钾电流的增强作用;与对照组大鼠相比,慢性缺氧大鼠肺内动脉平滑肌细胞钾电流下降,电流密度减小（690±450）pA/pFvs（420±250）pA/pF（P〈0.01）,膜电容增大到（4.29±1.78）pF（P〈0.01）,电流-电压（I-V）曲线下移;与缺血氧组相比,每日缺氧前口服Iptakalim,细胞膜电容减小为（3.09±1.71）（P〈0.01）,电流密度增大到（610±320）pA/pF（P〈0.01）。结论慢性缺氧抑制大鼠肺内动脉平滑肌细胞钾通道,灌服Iptakalim可拮抗慢性缺氧对KATP通道的抑制作用。

Objective To investigate effects of iptakalim,a novel KATP opener, on potassium currents in intra-pulmonary artery smooth muscles derived from chronic hypoxic rats. Methods Sprague-Dawley（SD） male rats were randomly divided into control group,chronic hypoxia group,treated Ⅰ group （chronic hypoxia and 0.75 mg·kg^-1·d^-1）,and treated Ⅱ group（chronic hypoxia and 1.5 mg·kg^-1·d^ -1）. Except the first group,the other three groups were put into hypoxic and normobaric chamber[（10±0.5）% O2,8 h·day^-1 and 6 day·week^-1 ] to establish rat models with chronic hypoxic pulmonary hypertension. Four weeks later,the effect s of iptakalim on potassium currents in intra-pulmonary arterial smooth muscle cells derived from rat were explored by using patch clamp technique （whole cell recording） after application of the drug in the bath. Results At 5 minutes after application of iptakalim at the concentrations of 0.1,1,10,100 μmol/ L, the potassium current amplitude in intra-pulmonary arterial SMC was enhanced in a concentration-dependent manner. The effects of iptakalim （10 μmol/L） on potassium current were blocked by glibenclamide （30 μmol/L）. The mean K^＋ current density-voltage relationship （I-V） curve in intra-pulmonary arterial SMC derived from hypoxia group rats shifted downward, compared with those from control rats. The membrane capacitance in the cells from simple hypoxic rats was increased （4.29±1.78 pF vs 3.16±1.86 pF, P〈0.05）,while the average current density was decreased（420±250 vs 690±450, P〈0.05） , compared with the cells from control rats. However, the values of membrane capacitance and K^＋ current density in the cells from the hypoxic rats pretreated with 4 weeks＇ iptakalim intake at the dosage of 0. 75 mg·kg^-1·d^-1 were close to those in control group. Conclusions The outward potassium currents in intra-pulmonary artery smooth muscle cells derived from rats could be enhanced by iptakalim, which could be blocked by glybenclimade,a specific KATP blocker. It is suggested that KATP channels in the intra-pulmonary arterial smooth muscle cells derived from rats with chronic hypoxic pulmonary hypertension be enhanced by iptakalim.