脱氢表雄甾酮对慢性缺氧大鼠肺动脉平滑肌细胞钙激活性钾通道的作用

目的　研究钾通道开放剂脱氢表雄甾酮 (DHEA)对慢性缺氧大鼠肺动脉平滑肌细胞钙激活性钾通道 (KCa)的作用和缺氧性肺动脉高压的降压作用。方法　 50只Wistar大鼠随机分为对照组 (A组 ,10只 )和慢性缺氧组 (B组 ) ,B组又随机分为B1、B2 、B3 、B4 组 (每组各 10只 ) ,B组大鼠均以常压缺氧 3周建立大鼠慢性缺氧肺动脉高压模型。采用急性酶分离法分离得到大鼠肺动脉平滑肌细胞(SMCs)。应用膜片钳技术 ,在对称性高钾溶液中 ,于急性分离的大鼠肺动脉平滑肌细胞的内面向外式膜片 (inside outpatch)上 ,分离出KCa电流。比较A组和B1组KCa电流活性 ;观察DHEA对B1组KCa通道电流的激活作用。应用右心插管技术 ,测定给药前后B2 、B3 、B4 组大鼠平均肺动脉压 (mPAP)和平均体动脉压 (mSAP)等血流动力学指标。结果　B组大鼠肺动脉平滑肌细胞KCa活性比A组大鼠显著降低 (P <0 0 1)。DHEA可明显激活慢性缺氧所抑制的B1组大鼠肺动脉平滑肌细胞的KCa电流。给缺氧大鼠静脉注射DHEA可明显降低其mPAP(P <0 0 1) ,而对mSAP无明显作用 (P >0 0 5)。结论　缺氧对KCa通道的抑制作用在缺氧 3周大鼠缺氧性肺动脉高压发病中起着重要作用 ;DHEA可直接激活KCa活性而拮抗慢性缺氧对KCa的抑制作用 ;DHEA对大鼠慢性缺氧性肺动脉高压可产

Effect of dehydroepiandrosterone on Ca2+-activated K+ channel of pulmonary arterial smooth muscle cells in pulmonary hypertensive rats

OBJECTIVE: To investigate the effects of dehydroepiandrosterone (DHEA) on Ca(2+)-activated K(+) (K(Ca)) channel and mean pulmonary arterial pressure (mPAP) in rats with chronic pulmonary hypertension. METHODS: Fifty Wistar rats were divided randomly into a normal group (group A, n = 10) and a chronic hypoxia group (group B, n = 40). The rats in group B were subdivided into group B(1), B(2), B(3), and B(4) (each n = 10) at random. The rats in group B were exposed to hypoxia (FiO(2) = 0.10 +/- 0.05) for 3 weeks, whereas the rats in group A maintained in air. Under normoxic conditions, the smooth muscle cells (SMCs) were isolated from the pulmonary artery by the acute enzymatic dissection methods. In the symmetrical high K(+) solution, the K(Ca) currents were separated with inside-out configuration using the patch clamp technique. The activity of K(Ca) currents in SMCs between group B(1) and group A was compared under normoxic conditions, and the effect of DHEA on K(Ca) channel from group B(1) was observed. The mPAP and mean systemic arterial pressure (mSAP) were determined by right cardiac catheterization in rats from group B(2), B(3), B(4) before and after DHEA was administrated to rats by intravenous injection. RESULTS: The activity of K(Ca) channel in group B rats was much lower than that in group A (P < 0.01). DHEA could reverse the reduced K(Ca) channel in group B(1) rats. The mPAP were decreased significantly (P < 0.01) after DHEA was administrated to the rats in group B(2), B(3), B(4) with little change on mSAP (P < 0.05). CONCLUSIONS: Persistent decrease of K(Ca) channel activity may take part in the development of chronic hypoxic pulmonary hypertension in rats. DHEA can decrease the increased mPAP induced by chronic hypoxia via activating K(Ca) channel of SMCs from pulmonary arteries.