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背景:严重的肺动脉高压是一种有着很高的死亡率的致残性疾病,其特征是肺部血管重塑以及右心室肥大。利用长期缺氧而导致肺动脉高压的内皮型一氧化氮合酶基因敲除的纯合子(NOS3(-/-))小鼠和野生型小鼠,以及野百合碱性肺动脉高压的大鼠,我们检测了可溶型鸟苷酸环化酶(sGC)的刺激因子。Bay41- 2272或其激活剂Bay58-2667是否会逆转肺部血管的重塑。方法与结果:在肺体外灌注系统中,Bay41-2272和Bay58-2667均能剂量依赖性地抑制急性缺氧导致的血压增高反应。野生型(NOS3(+/+))和NOS3基因敲除(NOS3(-/-))小鼠在氧气含量低于10％的环境中饲养21天或35天,外周肺动脉完全肌肉化程度的增高证明:两组小鼠均发生肺动脉高压、右心室肥大以及肺部血管重塑。从第21天到35天,分别用sGC的激活剂Bay58-2667(10 mg/kg/d)或刺激因子Bav41- 2272(10 mg/kg/d)处理野生型小鼠,能够明显减轻肺动脉高压、右心室肥大以及肺动脉的结构重塑。相反的,在NOS3基因敲除小鼠(NOS3(-/-))中长期使用sGC激活剂进行治疗却收效甚微。在注射野百合碱而导致严重肺动脉高压的大鼠中,这两种化合物均能明显逆转其血流动力学和结构上的的改变。结论:sGC的激活能够逆转野百合碱和长期缺氧性肺动脉高压所引起的血流动力学和结构的改变。而这种效果部分的依赖于NOS3产生的内源性一氧化氮。
BACKGROUND: Severe pulmonary hypertension is a disabling disease with high mortality characterized by pulmonary vascular remodeling and right ventricular hypertrophy. Homozygous (NOS3 (- / -)) mice and wild-type mice with long-term anoxia-induced endothelial nitric oxide synthase gene knockdown of pulmonary hypertension, and rats with wild lily alkaline pulmonary hypertension, we Stimulation factors for soluble guanylate cyclase (sGC) were tested. Bay41- 2272 or its activator Bay58-2667 will reverse the remodeling of pulmonary blood vessels. Methods and Results: Bay41-2272 and Bay58-2667 both inhibited the hypoxia-induced hypertension in a dose-dependent manner in the lung perfusion system. In the wild-type (NOS3 (+ / +)) and NOS3 knockout (NOS3 (- / -)) mice maintained for 21 days or 35 days with less than 10% Proof: Both groups of mice developed pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. From day 21 to day 35, treatment of wild-type mice with sGC activator Bay58-2667 (10 mg / kg / d) or stimulant Bav41-2272 (10 mg / kg / d) significantly reduced pulmonary hypertension Right ventricular hypertrophy, and pulmonary remodeling. In contrast, long-term treatment with sGC activators in NOS3 knockout mice (NOS3 (- / -)) failed with little success. Both compounds significantly reversed their hemodynamic and structural changes in rats injected with monocrotaline and causing severe pulmonary hypertension. CONCLUSIONS: Activation of sGC reverses hemodynamic and structural alterations induced by monocrotaline and chronic hypoxic pulmonary hypertension. And this effect is partly dependent on endogenous nitric oxide produced by NOS3.