Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats
Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats
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DOI：
10.1152/jappl.1997.83.4.1209
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发表时间：
1997-10-01
影响因子：
3.3
通讯作者：
Klinger, JR
中科院分区：
文献类型：
--
作者：
Hill, NS;Warburton, RR;Klinger, JR
内皮素-L(ET-I)是一种强大的血管活性和促有丝分裂的多肽，参与了多种形式的肺动脉高压的发病机制。我们假设，非特异性阻断ET受体将抑制野百合碱(MCT)诱导的大鼠肺动脉高压的发展。正常大鼠单次灌胃给予非特异性ET阻滞剂波生坦(100 mg/kg)，可完全阻断Big ET-1的肺血管收缩作用，部分阻断缺氧性肺血管收缩作用。3wk后，波生坦(200 mg/kg)皮下注射MCT105 mg/kg组大鼠右室收缩压(RVSP)、右室/体质量(RV/BW)和右室与左心室(LV)+室间隔(S)重量比值[RV/(LV+S)]均低于对照组，肺小动脉中层厚度百分比低于对照组。小剂量波生坦(100 mg/kg)对MCT或生理盐水注射后上述指标均无影响。波生坦使血浆ET-1水平升高，但对肺组织ET-1水平无影响。注射MCT后6d，波生坦(200 mg/kg)对肺湿重/干重比也无影响。在注射MCT后的最后10天，而不是注射MCT后的前11天，与注射MCT的对照组相比，波生坦降低了RV/(LV+S)。我们认为，ET-1参与了MCT诱导的肺动脉高压的发病过程，并且主要作用于炎症反应后期，而不是急性损伤阶段。
Endothelin-l (ET-I), a potent vasoactive and mitogenic peptide, has been implicated in the pathogenesis of several forms of pulmonary hypertension. We hypothesized that nonspecific blockade of ET receptors would blunt the development of monocrotaline (MCT)-induced pulmonary hypertension in rats. A single dose of the nonspecific ET blocker bosentan (100 mg/kg) given to intact rats by gavage completely blocked the pulmonary vasoconstrictor actions of Big ET-1 and partially blunted hypoxic pulmonary vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavaged once daily with bosentan (200 mg/kg) had lower right ventricular (RV) systolic pressure (RVSP), RV-to-body weight (RV/BW) and RV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios and less percent medial thickness of small pulmonary arteries than control MCT-injected rats. Lower dose bosentan (100 mg/kg) had no effect on these parameters after MCT or saline injection. Bosentan raised plasma ET-1 levels but had no effect on lung ET-1 levels. Bosentan (200 mg/kg) also had no effect on wet-to-dry lung weight ratios 6 days after MCT injection. When given during the last 10 days, but not the first 11 days of a 3-wk period after MCT injection, bosentan reduced RV/(LV+S) compared with MCT-injected controls. We conclude that ET-1 contributes to the pathogenesis of MCT-induced pulmonary hypertension and acts mainly during the later inflammatory rather than the acute injury phase after injection.