阿魏酸钠对野百合碱诱导肺动脉高压大鼠的保护作用
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摘要
目的:肺动脉高压(pulmonary arterial hypertension,PAH)是指以肺血管阻力进行性增高,并导致右心室衰竭及死亡为特征的一组疾病。内皮功能障碍是肺动脉高压的核心病理生理改变,引起内皮和平滑肌细胞过度增殖导致管腔狭窄。既往研究表明阿魏酸钠有抗血栓、抗血小板聚集和抗氧化的作用,阿魏酸钠能够通过增加血管NO生成而改善内皮功能。有临床经验表明阿魏酸钠对于慢性阻塞性肺病及肺心病有一定的疗效,但阿魏酸钠对肺动脉高压是否有保护作用还不明确。故我们通过野百合碱建立肺动脉高压大鼠模型,验证其是否有保护作用。
方法:共50只Sprague-Dawley雄性大鼠被随机分为4组接受不同的处理,正常对照组(n=8):第一日皮下注射生理盐水2ml/Kg,第2—35天每日一次蒸馏水2ml/Kg灌胃;.阳性对照组(n=12):第1天腹腔注射野百合碱60 mg/kg,第2—35天每日一次蒸馏水2ml/Kg灌胃;预防组(n=15):室内饲养,第1天腹腔注射野百合碱60 mg/kg,第2—35天每日一次阿魏酸钠0.3g/Kg灌胃;.治疗组(n=15):第1天腹腔注射野百合碱60 mg/kg,第2—21天每日一次蒸馏水2ml/Kg灌胃;第22—35天每日一次阿魏酸钠0.3g/Kg灌胃。
在第35天时,在麻醉状态下右心导管法,测定大鼠的血流动力学指标,右室收缩压、颈动脉平均压、心率,留取血标本测定血浆ET-1水平,处死大鼠后取心脏,测定右室/(左室+室间隔)重量之比,留取肺组织作Western Blot测定内皮型一氧化氮合酶eNOS的在大鼠肺组织中的表达改变,以及作肺血管病理学切片,观察肺血管的病理变化,并测定血管中膜厚度。
结果:在注射野百合碱35天后,所有8只正常对照均存活(100%,8/8),阳性对照组有7只存活(生存率46.7%,7/15),预防组有8只存活(生存率66.7%,8/12),治疗组有8只存活(生存率53.3%,8/15),大鼠死因均为右心衰竭,大鼠的生存率无统计学差异。与阳性对照组相比,阿魏酸钠显著降低预防组的右室收缩压(77.0? 0.8 vs.59.5?.1mmHg),心率和动脉血压无显著变化,降低了预防组右室/(左室+室间隔)重量之比(0.697.10 vs.0.487.10,p＜0.05),减轻了预防组大鼠的肺血管内膜的增殖,显著降低血管中膜厚度(11.57.5 vs.9.17.4,p＜0.05),但血浆ET-1水平在预防和治疗组均仅有降低趋势,无统计学差异。阿魏酸钠使预防组和治疗组的eNOS表达,均较阳性对照组显著恢复(0.56? 0.2 vs.41.21?0.59Vs.1.13 ? 0.50,p＜0.05)。
结论:阿魏酸钠对野百合碱诱导肺动脉高压大鼠有一定保护作用,能改善血流动力学指标,降低其右室收缩压,降低右心室负荷,降低右室/(左室+室间隔)重量之比,其机制可能与eNOS表达恢复相关。
Background:Pulmonary arterial hypertension is a fatal disorder that is associated with remodeling of the pulmonary vasculature.Endothelial dysfunction plays an important role in the progression of pulmonary arterial hypertension.Previous studies showed that sodium ferulate can improve endothelial function by increasing nitric oxide(NO) production.Sodium ferulate has antithrombotic,platelet aggregation inhibitory and antioxidant activities.We hypothesized that daily supplemenation of sodium ferulate attenuate monocrotaline induced pulmonary artery hypertension in rats.
Methods:Our hypotheses was tested in a modle of pulmonary arterial hypertension induced with monocrotaline in rats.Fifty rats were randomly divided into four groups: normal control(treated with saline and distilled water,n=8 ),other rats received monocrotaline injection were randomly assigned to preventive group(treated with sodium ferulate,n=12),positive control group(treated with distilled water,n=15) and treatment group(treated with distilled water then with sodium ferulate,n=15).We measuered the right ventricular systolic pressure,the ratio of right ventricular weight to weight of the left ventricle plus septum.We investigated the changes in the expression of endothelial nitric oxide synthase(eNOS) in lung and endothelin-1 (ET-1) level in plasma,as well as the histological changes in pulmonary arteries in the different groups.
Result:Up to the day 35,pulmonary arterial hypertension was successful developed in the positive control group rats.Compared with positive control group,sodium ferulate significantly reduced right ventricle systolic pressure(77.0? 0.8 vs. 59.5?.1mmHg,p＜0.05) and the ratio of right ventricular weight to weight of the left ventricle plus septum in the preventive group(0.68?.10 vs.0.48?.10,p＜0.05). Sodium ferulate significantly restored the expression of eNOS in lung in the preventive and reversal groups.However,sodium ferulate didn't significantly reduce the plasma ET-1 level in the preventive and reversal groups.
Conclusion:sodium ferulate attenuated pulmonary arterial hypertension in the monocrotaline-treated rats.The protective effects may be associated with the restoration of expression of eNOS expression.
方法:共50只Sprague-Dawley雄性大鼠被随机分为4组接受不同的处理,正常对照组(n=8):第一日皮下注射生理盐水2ml/Kg,第2—35天每日一次蒸馏水2ml/Kg灌胃;.阳性对照组(n=12):第1天腹腔注射野百合碱60 mg/kg,第2—35天每日一次蒸馏水2ml/Kg灌胃;预防组(n=15):室内饲养,第1天腹腔注射野百合碱60 mg/kg,第2—35天每日一次阿魏酸钠0.3g/Kg灌胃;.治疗组(n=15):第1天腹腔注射野百合碱60 mg/kg,第2—21天每日一次蒸馏水2ml/Kg灌胃;第22—35天每日一次阿魏酸钠0.3g/Kg灌胃。
在第35天时,在麻醉状态下右心导管法,测定大鼠的血流动力学指标,右室收缩压、颈动脉平均压、心率,留取血标本测定血浆ET-1水平,处死大鼠后取心脏,测定右室/(左室+室间隔)重量之比,留取肺组织作Western Blot测定内皮型一氧化氮合酶eNOS的在大鼠肺组织中的表达改变,以及作肺血管病理学切片,观察肺血管的病理变化,并测定血管中膜厚度。
结果:在注射野百合碱35天后,所有8只正常对照均存活(100%,8/8),阳性对照组有7只存活(生存率46.7%,7/15),预防组有8只存活(生存率66.7%,8/12),治疗组有8只存活(生存率53.3%,8/15),大鼠死因均为右心衰竭,大鼠的生存率无统计学差异。与阳性对照组相比,阿魏酸钠显著降低预防组的右室收缩压(77.0? 0.8 vs.59.5?.1mmHg),心率和动脉血压无显著变化,降低了预防组右室/(左室+室间隔)重量之比(0.697.10 vs.0.487.10,p＜0.05),减轻了预防组大鼠的肺血管内膜的增殖,显著降低血管中膜厚度(11.57.5 vs.9.17.4,p＜0.05),但血浆ET-1水平在预防和治疗组均仅有降低趋势,无统计学差异。阿魏酸钠使预防组和治疗组的eNOS表达,均较阳性对照组显著恢复(0.56? 0.2 vs.41.21?0.59Vs.1.13 ? 0.50,p＜0.05)。
结论:阿魏酸钠对野百合碱诱导肺动脉高压大鼠有一定保护作用,能改善血流动力学指标,降低其右室收缩压,降低右心室负荷,降低右室/(左室+室间隔)重量之比,其机制可能与eNOS表达恢复相关。
Background:Pulmonary arterial hypertension is a fatal disorder that is associated with remodeling of the pulmonary vasculature.Endothelial dysfunction plays an important role in the progression of pulmonary arterial hypertension.Previous studies showed that sodium ferulate can improve endothelial function by increasing nitric oxide(NO) production.Sodium ferulate has antithrombotic,platelet aggregation inhibitory and antioxidant activities.We hypothesized that daily supplemenation of sodium ferulate attenuate monocrotaline induced pulmonary artery hypertension in rats.
Methods:Our hypotheses was tested in a modle of pulmonary arterial hypertension induced with monocrotaline in rats.Fifty rats were randomly divided into four groups: normal control(treated with saline and distilled water,n=8 ),other rats received monocrotaline injection were randomly assigned to preventive group(treated with sodium ferulate,n=12),positive control group(treated with distilled water,n=15) and treatment group(treated with distilled water then with sodium ferulate,n=15).We measuered the right ventricular systolic pressure,the ratio of right ventricular weight to weight of the left ventricle plus septum.We investigated the changes in the expression of endothelial nitric oxide synthase(eNOS) in lung and endothelin-1 (ET-1) level in plasma,as well as the histological changes in pulmonary arteries in the different groups.
Result:Up to the day 35,pulmonary arterial hypertension was successful developed in the positive control group rats.Compared with positive control group,sodium ferulate significantly reduced right ventricle systolic pressure(77.0? 0.8 vs. 59.5?.1mmHg,p＜0.05) and the ratio of right ventricular weight to weight of the left ventricle plus septum in the preventive group(0.68?.10 vs.0.48?.10,p＜0.05). Sodium ferulate significantly restored the expression of eNOS in lung in the preventive and reversal groups.However,sodium ferulate didn't significantly reduce the plasma ET-1 level in the preventive and reversal groups.
Conclusion:sodium ferulate attenuated pulmonary arterial hypertension in the monocrotaline-treated rats.The protective effects may be associated with the restoration of expression of eNOS expression.
引文
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