虎杖苷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 of polydatin on hypoxic pulmonary hypertension in rats and the mechanism

目的:研究虎杖苷(PD)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6组,即对照组、低压低氧组、预防组(ip 5,10和20 mg.kg-1PD)和阳性对照组(ig1.7 mg.kg-1西地那非)。建立低压低氧性肺动脉高压大鼠模型,观察PD干预21 d后大鼠肺动脉平均压(mPAP),右心肥厚指数RV/(LV+S)和肺血管形态学的改变,以及大鼠血清、肺组织中一氧化氮(NO)含量、一氧化氮合酶(NOS)活性。结果:①检测PD干预21 d大鼠mPAP,RV/(LV+S),PAMT,SMC,WT%和WA%各指标:对照组依次为(18.35±2.39)mmHg,(21.93±1.66)%,(13.49±2.77)μm,(5.91±1.23),(31.04±3.43)%和(42.83±4.36)%;低压低氧组为(32.05±3.19)mmHg,(36.94±2.67)%,(27.91±4.43)μm,(9.32±1.67),(49.41±4.59)%和(71.72±4.64)%,显著高于对照组(P<0.01);PD中、高剂量组和阳性对照组各指标明显低于低压低氧组(P<0.05或P<0.01)。②血清中NO含量、NOS和cNOS活性:对照组依次为(66.34±5.41)μmol.L-1,(23.18±1.44)U.mL-1和(14.51±1.46)U.mL-1;低压低氧组为(41.07±3.71)μmol.L-1,(12.59±1.50)U.mL-1和(7.19±1.85)U.mL-1,显著低于对照组(P<0.01);肺组织匀浆中NO含量、NOS和cNOS活性:对照组依次为(0.397±0.060)μmol.(g prot)-1,(0.752±0.044)U.(mg prot)-1和(0.511±0.064)U.(mg prot)-1;低压低氧组为(0.316±0.046)μmol.(gprot)-1,(0.605±0.069)U.(mg prot)-1和(0.387±0.030)U.(mg prot)-1,显著低于对照组(P<0.01);而PD中、高剂量组和阳性对照组血清和肺组织匀浆中各指标均高于低压低氧组(P<0.05或P<0.01)。结论:PD给药21 d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血清、肺组织中NO含量和增强NOS活性有关。

Objective ：To investigate the preventive effect of polydatin （PD） on hypoxic pulmonary hypertension in rats and the possible mechanism. Methods：Sixty male Sprague-Dawley rats were randomly divided into six groups. After hypotensive and hypoxic pulmonary hypertension （HPH） was induced, rats were ip injected with PD at 5, 10 and 20 mg·kg^-1 , or oral silaenafil at 1.7 mg·kg^-1 （ positive control）. Mean pulmonary artery pressure （ mPAP）, ratio of right ventricular/（ lift ventricular ± interventricular septnm） [ RV/（ LV ± S） ], morphological change of pulmonary vessel were observed. Nitric oxide （NO） content and nitric oxide synthase （NOS） were de-tected in serum and lung homogenate of rats treated with PD for 21days. Results：（1）The values of mPAP, RV/（LV ±S）, PAMT, SMC, WT% , and WA% were （18.35 ±2.39） mmHg, （21.93 ±1.66）%, （13.49 ±2.77）μm, （5.91±1.23）, （31.04 ±3.43）% and （42.83 ±4.36）% in control rats, and were （32.05 ±3. 19） mmHg, （36.94 ±2.67）%, （27.91 ±4.43）μm, （9.32±1.67）, （49.41 ±4.59）% and （71.72 ±4.64）% in HPH rats （P 〈0.01 vs control）. All the indexes were obviously lower in middle- and high-dose PD groups and positive control group than in HPH group （P 〈 0.05 or P 〈 0.01）. （2）The values of NO, NOS, cNOS in serum were （66.34±5.41） mol·L^-1, （23.18-1.44） U·mL^-1 and （14.51 ±1.46） U·mL^-1 in control group, and were （41.07±3.71） mol·L^-1, （12.59±1.50） U·mL^-1 and （7.19±1.85）U·mL^-1 in HPH group （P 〈0.01 vs control）. The values of NO, NOS, cNOS in lung homogenate were （0. 397 ± 0. 060） μmol· （ g prot） ^-1, （0. 752 ± 0. 044） U·（ mg prot） ^-1 and （0.511 ± 0. 064） U· （ mg prot） ^-1 in control group, and were （0.316 ± 0. 046） μmol· （gprot） ^-1, （0.605 ±0.069） U·（mgprot） ^-1 and （0.387±0.030） U· （ mg prot） ^-1in HPH group （P〈0.01 vs control）. The all indexes were significantly higher in middle- and high-dose PD groups and positive control group than in HPH group （P 〈0.05 or P 〈 0.01 ）. Conehlsion：PD administered for 21 d can effectively prevent HPH and pulmonary vascular remodeling in rats with pulmonary hypertension; the mechanism may related to up-regulating NO content and NOS activity in serum and lung homogenate.