The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6. We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.
摘要
本研究的目的是调查一种膜通透性超氧化物歧化酶模拟物tempol单独添加或与一氧化氮（NO）供体吗多明联合添加时，是否能预防慢性低氧大鼠肺动脉高压（PH）的发展。2. 持续2周的慢性低压低氧（10%氧气）使右心室收缩压（RVSP）、右心室和肺湿重增加。慢性低氧大鼠离体的近端而非远端肺动脉中，乙酰胆碱（ACh）和吗多明代谢产物SIN-1引起的舒张功能受损。3. 用tempol（饮用水中86 mg x kg(-1) 天(-1)）治疗可使RVSP恢复正常并减轻右心室肥厚，而全身血压、肺和肝脏重量以及肺动脉ACh舒张功能减弱则未改变。4. 用吗多明（饮用水中15 mg x kg(-1) 天(-1)）治疗具有与tempol相同的效果，但肝脏重量减轻，肺动脉中钾和U46619诱发的血管收缩增加。与单独使用tempol相比，联合使用tempol和吗多明没有额外效果。这些治疗未使肺动脉ACh舒张功能恢复正常。5. 与常氧大鼠相比，低氧大鼠肺动脉的中膜与管腔直径比更大，并且tempol、吗多明或tempol与吗多明联合治疗均未使其逆转。6. 我们得出结论，tempol与吗多明一样，能够纠正大鼠低氧模型中的RVSP并减轻右心室重量。肺小动脉的功能和结构特性受影响较小。结果支持超氧化物歧化酶模拟物可能是治疗PH的有用手段这一可能性。
