Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat
Celecoxib but not the combination of celecoxib+atorvastatin prevents the development of monocrotaline-induced pulmonary hypertension in the rat
复制标题
塞来昔布而非塞来昔布阿托伐他汀组合可预防大鼠野百合碱诱导的肺动脉高压的发生
DOI：
10.1007/s00210-008-0298-3
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
M. Bardou
中科院分区：
文献类型：
--
作者：
Z. Rakotoniaina;P. Guérard;F. Lirussi;L. Rochette;M. Dumas;F. Goirand;M. Bardou
本研究旨在评估考克斯-2抑制剂塞来昔布和HMG-CoA还原酶抑制剂阿托伐他汀对野百合碱（MC）诱导的大鼠肺动脉高压的影响，以及两者的相关性。将塞来昔布（Cib，25 mg kg−1 day−1）、阿托伐他汀（AS，10 mg kg−1 day−1）或溶剂单独或联合经口给予注射或未注射MC（60 mg/kg腹腔注射）的Wistar雄性大鼠，持续26天。在4周时，注射MC的大鼠出现严重的肺动脉高压，肺/体重比（L/BW）增加，右心室压力增加，（MC组和对照组的RVP（mmHg）分别为31 ± 3和14 ± 1，P < 0.05）和右心室/左心室+室间隔重量比（RV/LV+S）与乙酰胆碱和硝普钠减少相关。体外诱导肺动脉血管舒张。高血压组肺动脉壁厚与外径比值为0.42 ± 0.01，对照组为0.24 ± 0.01，P < 0.001。整个肺eNOS的表达减少，并增加细胞凋亡，评估裂解caspase-3的表达，证明了蛋白质印迹。CIB（MC+Cib组和MC组的RVP分别为19 ± 3和31 ± 3 mmHg，P < 0.05），但AS和AS+Cib组均未明显抑制肺动脉高压的形成（P < 0.05），虽然通过L/BW和RV/（LV+S）比值评估，三种治疗对MC诱导的肺和右心室肥大具有保护作用，P < 0.05。AS、Cib和AS+Cib治疗可减轻MC诱导的肺内小动脉壁增厚（MC、MC+AS、MC+Cib和MC+AS+Cib组分别为0.42 ± 0.01、0.24 ± 0.01、0.26 ± 0.01和0.28 ± 0.01，P < 0.001）。在对照组大鼠中，Cib减少乙酰胆碱诱导的肺动脉血管舒张。Cib或AS治疗MC大鼠均不能改善乙酰胆碱诱导的肺动脉舒张，而两者联合治疗则显著加重了肺动脉舒张（P < 0.05）。AS可抑制MC大鼠全肺细胞凋亡（AS，P < 0.05），部分恢复eNOS表达（AS，P < 0.05）。总之，塞来昔布对野百合碱诱导的肺动脉高压和右心室肥大的发展具有有益作用。塞来昔布的这些有益作用可能至少部分通过其对肺动脉增厚和肺肥大的作用来解释，即使其对肺动脉血管舒张和全肺eNOS表达或凋亡没有任何影响。塞来昔布和阿托伐他汀联合用药不能预防MC诱导的肺动脉高压，降低内皮依赖性血管舒张，并显示RVP增加的趋势，值得进一步研究。
The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg−1 day−1), atorvastatin (AS, 10 mg kg−1 day−1) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 ± 3 and 14 ± 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 ± 0.01 vs 0.24 ± 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 ± 3 and 31 ± 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension (P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively (P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 ± 0.01, 0.24 ± 0.01, 0.26 ± 0.01 and 0.28 ± 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it (P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies.
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