ATP钾通道开放剂对大鼠慢性低氧性肺动脉高压的作用

目的：研究ATP敏感性钾通道开放剂左旋克罗卡琳（levcromakalim)和克罗卡啉（cromakalim)对慢性低氧大鼠肺动脉平滑肌细胞钾通道（KATP)和低氧性肺动脉高压的作用。方法：90只Wistar大鼠随机分为正常对照组（15只）和低氧组（75只）。应用膜片钳技术，在对称性高钾溶液中，将急性分离的大鼠肺动脉平滑肌细胞的内面向外式膜片上，分离出ATP敏感性KATP电流。应用右心插管技术，测定给药前、后大鼠平均肺动脉压（mPAP)。结果：慢性低氧3周大鼠肺动脉平滑肌细胞KATP通道活性与正常组大鼠比较无明显变化。但钾通道开放剂levcromakalim和cromakalim可明显激活慢性低氧大鼠肺动脉平滑肌细胞KATP电流。给低氧大鼠静脉注射levcromakalim和cromakalim，可对其mPAP产生剂量依赖性的降压作用，而对平均体动脉压也有一定的降低作用。结论：虽然KATP可能没有直接参与大鼠慢性低氧性肺动脉高压的产生，但levcromakalim和cromakalim可通过激活KATP通道而拮抗低氧对其它钾通道的抑制作用，levcromakalim和cromakalim可降低慢性缺氧大鼠低氧性肺动脉高压。

Effect of levcromakalim and cromakalim on ATP-sensitive K+ channel of pulmonary arterial smooth muscle cells in pulmonary hypertensive rats

OBJECTIVE: To investigate the effect of levcromakalim and cromakalim on ATP-sensitive K(+) channel (K(ATP)) and mean pulmonary arterial pressure (mPAP) in rats with chronic hypoxic pulmonary hypertension. METHODS: Ninety Wistar rats were divided randomly into a normal group (15) and a chronic hypoxia group (75). Rats in the hypoxia group were exposed to hypoxia (FiO(2) = 0.10 +/- 0.05) for 3 weeks, whereas rats in the normal group maintained in air. The currents of K(ATP) of pulmonary artery smooth muscle cells (PASMCs) from both the chronic hypoxic and the normal groups were observed using patch-clamp technique inside-out configuration, and the effect of levcromakalim and cromakalim on K(ATP) from chronic hypoxic group was determined under normoxic conditions. The mPAP and mSAP were determined by catheterization in hypoxic rats before and after levcromakalim and cromakalim were administrated respectively to the rats with doses ranging from 100 micro g/kg to 200 micro g/kg intravenously. RESULTS: Chronic hypoxia had little effect on the activity of K(ATP) in the chronic hypoxic rats. Levcromakalim and cromakalim remarkably activated the K(ATP) in chronic hypoxic rats. A dose-dependent decreasing effect on mPAP was elicited by levcromakalim and cromakalim in the hypoxic rats. CONCLUSION: Although K(ATP) activity is probably not directly involved in the development of chronic hypoxic pulmonary hypertension in rats, both levcromakalim and cromakalim decrease the increased mPAP induced by chronic hypoxia by activating K(ATP) of SMCs from pulmonary arteries, therefore diminishing the inhibitory effect of hypoxia on other K(+) channels.