川芎嗪对大鼠低压低氧性肺动脉高压的预防作用及初步机制探讨

Preventive Effect and Underlying Mechanism of Tetramethylpyrazine on Hypobaric and Hypoxic Pulmonary Hypertension in Rats

目的:研究川芎嗪(TMP)对慢性低压低氧性肺动脉高压模型大鼠的防治作用及其机制。方法:将雄性SD大鼠随机分为3组,即正常对照组、低压低氧组与川芎嗪组(100 mg·kg^(-1)·d^(-1))。建立低压低氧性肺动脉高压大鼠模型,观察TMP干预后大鼠平均肺动脉压力(mP AP)、左颈总动脉插管测平均颈动脉压(mC AP)、右心室肥厚指数(RVHI)和肺血管形态学的改变,计算肺细小动脉管壁厚度占血管外径的百分比(WT%)和管壁面积占血管总面积的百分比(WA%),以及大鼠血清中一氧化氮(NO)、内皮素-1(ET-1)、缺氧诱导因子-1α(HIF-1α)与血管内皮生长因子(VEGF)水平。结果:检测TMP干预21 d,大鼠mP AP、RVHI、WT%和WA%各指标比较,低压低氧组显著高于正常对照组(P<0.05或P<0.01),川芎嗪组显著低于低压低氧组(P<0.05或P<0.01)。低压低氧条件对颈动脉压力mC AP影响不大,组间比较差异均无统计学意义(P>0.05)。血清中NO含量比较,低压低氧组显著低于正常对照组(P<0.05),川芎嗪组显著高于低压低氧组(P<0.05)。血清中ET-1、HIF-1α与VEGF含量比较,低压低氧组显著高于正常对照组(P<0.05),川芎嗪组显著低于低压低氧组(P<0.05)。结论:TMP可有效预防大鼠低压低氧导致的肺动脉高压和肺小动脉的结构重建,其作用机制可能与上调大鼠血清NO含量和下调ET-1、HIF-1α与VEGF活性有关。

Objective： To investigate the preventive effect of tetramethylpyrazine （TMP） on hypoxic pulmonary hypertension in rats and the underlying mechanism. Methods： Thirty-six male Sprague-Dawley rats were randomly divided into three groups： the normal control group, hypobaric and hypoxic group and TMP group （ 100 mg ·kg^-1 ·d^-1 ）. After the animal models of hypobaric and hypoxic pulmonary hypertension were established, mean pulmonary artery pressure （ mPAP）, mean carotid artery pressure （ mCAP）, ratio of right ventricular/（lift ventricular ＋ interventricular septum） （RVHI） and morphological changes of pulmonary vessels were observed and the rates of wall thickness/external diameter （ WT% ） and wall area/total vascular area （WA%） were calculated. The contents of nitric oxide （ NO）, endothelin-1 （ ET-1 ）, hypoxic-inducible factor-1 （ HIF-1 ） and vascular endothelial growth factor （VEGF） were detected in serum after the 21-day treatment with TMP. Results： The values of mPAP, RVHI, WT% and WA% of hypobaric and hypoxic group were significant higher than those of the normal control group （ P 〈 0.05 or P 〈 0.01 ）, and those of TMP group were obviously lower than those of hypobaric and hypoxic group （P 〈 0.05 or P 〈 0.01 ）. The condition of hypobaric and hypoxic had no significant effect on mCAP, and there were no significant differences among the groups （P 〉 0.05）. The values of NO in serum of hypobaric and hypoxic group was lower than those of the normal control group （P 〈 0.05） and those of TMP group were obviously higher than those of hypobaric and hypoxie group （P 〈 0.05 ）. The values of ET-1, HIF-1α and VEGF in serum of hypobarie and hypoxic group were higher than those of the normal control group （ P 〈 0.05 ） and those of TMP group were obviously lower than those of hypobaric and hypoxie group （ P 〈 0.05 ）. Conclusion： TMP can effectively prevent pulmonary hypertension induced by hypobaric and hypoxic and structural remodeling of pulmonary arterioles. The mechanism may be related to the content up-regulation of NO and activity down-regulation of ET-1, HIF-1α and VEGF in serum of rats.