慢性低氧性肺动脉高压大鼠内源性一氧化氮代谢及其外源性吸入的研究

目的:研究一氧化氮(NO)在大鼠慢性低氧性肺动脉高压发生发展中的代谢变化,观察外源性吸入NO对肺血流动力学的疗效。方法:67只SD雄性成年大鼠,随机分为7组:常氧对照组(n=9),慢性间断性低氧(6h/d,7d/周)1周组(n=7),低氧2周组(n=11),低氧3周组(n=11),L-NAME(NO合成酶抑制剂,30mg/kg,灌饲)处理组(n=10),L-Arg(NO合成前质,10mg/kg,灌饲)处理组(n=9),NO吸入(0.0004%,20min)组(n=10)。插管测肺动脉平均压(MPAP),分离右心室(R)、室间膈+左心室(S+L),计算R/(S+L)(g/g)和R/Wt(Wt:体重,g/kg)。结果:①低氧1周组MPAP显著高于对照组,低氧2周时更高,R/(S+L)和R/Wt也显著高于对照组;②血浆NO₂^-/NO₃^-含量在低氧2周组显著高于对照组,而在低氧3周组显著低于低氧2周组和低氧1周组;低氧1周,血浆ET-1含量显著高于对照组,血浆ET-1含量与MPAP和R/(S+L)均呈显著正相关,r分别为0.43和0.46,P值均＜0.01;③L-NAME组大鼠血浆NO₂^-/NO₃^-含量降低33.2%,R/(S+L)显著增加15.2%,P＜0.05;④L-Arg组大鼠血浆NO₂^-/NO₃^-含量和PAPM无显著改变,但R/(S+L)降低8.7%,P＜0.05;⑤吸入NO,MPAP降低17.8%,P＜0.01。结论:内源性NO在慢性低氧早期(1-2周)继发性增加,但进一步低氧时则减少,血浆ET-1含量的增加在低氧性心肺血管重建中可能具有重要意义,吸入低浓度NO对以肺血管增生和右心室肥大为主要基础的肺动脉高压仍具有明显降低作用。

Changes in endogenous nitric oxide and effects of inhaled nitric oxide on pulmonary artery hypertension in chronically hypoxic rats

AIM: To investigate the role of nitric oxide (NO)in the development of chronically hypoxic pulmonary artery hypertension (PAH) and the hemodynamic effects of inhaled NO on pulmonary circulation. METHODS: 67 male adult SD rats were randomly divided into 7 groups: (1) control (n=9);(2) chronically intermitent hypoxia (CIH, 6 h/d, 7 d/w) 1 week(n=7); (3) CIH 2 weeks (n=11); (4) CIH 3 weeks (n=11); (5) CIH 1 week+L-NAME (NO synthase inhibitor, 30 mg/kg, by gavage, n=10); (6)CIH 3 weeks+L-Arg (NO precursor, 10 mg/kg, by gavage, n=9); (7) CIH 3 weeks+inhaled NO (0.0004% for 20 min, n=10) to determine the mean pulmonary artery pressure (MPAP), weigh the right ventricle (R) and ventricular segment plus left ventricle (S+L), and calculate R/(S+L) (g/g) and R/Wt (Wt: body weight, g/kg). RESULTS: 1.MPAP increased compared with control when CIH 1 week, reaching the highest when CIH 2 weeks; R/(S+L) and R/Wt also increased notably when CIH 1 week (P＜0.01); 2. The level of plasma NO₂^-/NO₃^- elevated significantly when CIH 2 weeks, but fell when CIH 3 weeks; the content of plasma ET-1(endothelin-1) also increased significantly. The level of plasma ET-1 correlated with R/(S+L) and R/Wt, r=0.43 and 0.46, respectively, both P＜0.01; 3. The level of plasma NO₂^-/NO₃^- droped 33.2 % (P＜0.01) after treatment with L-NAME, with R/(S+L) increasing 15.2 % (P＜0.05); 4. L-Arg decreased the MPAP 17.8 %(P＜0.01). CONCLUSION: The endogenous NO release increases at early stage (1-2 weeks) of chronic hypoxia, but falls at the prolonged stage; the elevated level of plasma ET-1 possibly plays an important role in remodeling of chronically hypoxic pulmonary vessels and ventricle; inhaled NO significantly decreases the chronically hypoxic PAH.