Manipulation of nitric oxide (NO) may enable control of progression and treatment of pulmonary hypertension (PH). Several approaches may modulate the NO-cGMP pathway in vivo. Here, we investigate the effectiveness of 3 modulatory sites: (i) the amount of l-arginine; (ii) the size of plasma NO stores that stimulate soluble guanylate cyclase; (iii) the conversion of cGMP into inactive 5′-GMP, with respect to hypoxia, to test the effectiveness of the treatments with respect to hypoxia-induced PH. Male rats (n = 80; 10/group) maintained in normoxic (21% O₂) or hypoxic chambers (10% O₂) for 14 days were subdivided in 4 sub-groups: placebo, l-arginine (20 mg/ml), the NO donor molsidomine (15 mg/kg in drinking water), and phoshodiesterase-5 inhibitor sildenafil (1.4 mg/kg in 0.3 ml saline, i.p.). Hypoxia depressed homeostasis and increased erythropoiesis, heart and right ventricle hypertrophy, myocardial fibrosis and apoptosis inducing pulmonary remodeling. Stimulating anyone of the 3 mechanisms that enhance the NO-cGMP pathway helped rescuing the functional and morphological changes in the cardiopulmonary system leading to improvement, sometimes normalization, of the pressures. None of the treatments affected the observed parameters in normoxia. Thus, the 3 modulatory sites are essentially similar in enhancing the NO-cGMP pathway, thereby attenuating the hypoxia-related effects that lead to pulmonary hypertension.

控制一氧化氮 (NO) 可以控制肺动脉高压 (PH) 的进展和治疗。几种方法可以在体内调节 NO-cGMP 途径。在这里，我们研究了 3 个调节位点的有效性：（i）l-精氨酸的量；(ii) 刺激可溶性鸟苷酸环化酶的血浆 NO 储存量；(iii) cGMP 转化为无活性的 5'-GMP，就缺氧而言，以测试治疗对缺氧诱导的 PH 的有效性。雄性大鼠（n = 80；10/组）在常氧（21% O ₂）或缺氧室（10% O ₂）中维持 14 天，分为 4 个亚组：安慰剂、l-精氨酸（20 mg/ml）、NO 供体 molsidomine（15 mg/kg 在饮用水中）和磷酸二酯酶 5 抑制剂西地那非（1.4 mg/kg 在 0.3 ml 盐水中，ip）。缺氧抑制体内平衡并增加红细胞生成、心脏和右心室肥大、心肌纤维化和诱导肺重塑的细胞凋亡。刺激增强 NO-cGMP 通路的 3 种机制中的任何一种都有助于挽救心肺系统的功能和形态变化，从而导致压力的改善，有时甚至是正常化。没有一种治疗影响常氧中观察到的参数。因此，这 3 个调节位点在增强 NO-cGMP 途径方面基本相似，从而减弱了导致肺动脉高压的缺氧相关效应。