Department of Pharmacology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan; Laboratory of Molecular and Pathological Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Laboratory of Molecular and Pathological Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
Life Sci. 2018 Jun 15;203:203-209. doi: 10.1016/j.lfs.2018.04.045. Epub 2018 Apr 26.
In this study, we examined whether a disruption in the balance between nitric oxide (NO)-sensitive and -insensitive soluble guanylate cyclase (sGC) is observed in pulmonary hypertension (PH) and whether treatment with NO-enhancing drugs can halt disease progression.
Rats were injected subcutaneously with saline or 60 mg/kg monocrotaline (MCT). At 14 days after injection, the vascular reactivity of isolated extralobar pulmonary arteries was assessed by organ chamber technique. In a separate experiment, isosorbide mononitrate (0.3 or 1 g/L) or sodium nitrite (30 or 300 mg/L) was administered in drinking water for the last 14 days (from day 15 to day 28), and their therapeutic potential was evaluated.
The NO-sensitive sGC stimulant BAY 41-2272 and the NO-insensitive sGC stimulant BAY 60-2770 both relaxed the pulmonary arteries, which was comparable between saline- and MCT-injected rats. Treatment with isosorbide mononitrate suppressed the MCT-induced right ventricular systolic pressure (RVSP) elevation and pulmonary arterial medial thickening but not right ventricular hypertrophy. However, the beneficial effects on RVSP and pulmonary vascular remodeling were not observed when a high dose was administered. The same results were obtained following the sodium nitrite treatment. Interestingly, NO-enhancing drugs did not increase plasma nitrite plus nitrate levels at a dose that provided the greatest therapeutic advantage.
These findings suggest that the balance between NO-sensitive and -insensitive sGC is not disrupted in the early stage of MCT-induced PH. Furthermore, supplementation with an adequate amount of NO may be a useful therapy to prevent the progression of PH.
在这项研究中，我们研究了肺动脉高压（PH）是否存在一氧化氮（NO）敏感型和非敏感型可溶性鸟苷酸环化酶（sGC）之间的平衡破坏，以及NO 增强药物的治疗是否可以阻止疾病进展。
大鼠皮下注射生理盐水或 60mg/kg 单环酸（MCT）。注射后 14 天，通过器官室技术评估离体肺外肺动脉的血管反应性。在另一项实验中，14 天（从第 15 天到第 28 天）饮用水中给予异山梨醇单硝酸酯（0.3 或 1g/L）或亚硝酸钠（30 或 300mg/L），并评估其治疗潜力。
NO 敏感型 sGC 激动剂 BAY 41-2272 和 NO 非敏感型 sGC 激动剂 BAY 60-2770 均可松弛肺动脉，生理盐水和 MCT 注射大鼠之间的松弛作用相当。异山梨醇单硝酸酯治疗可抑制 MCT 引起的右心室收缩压（RVSP）升高和肺动脉中层增厚，但不能抑制右心室肥厚。然而，高剂量给药时未观察到对 RVSP 和肺血管重塑的有益作用。亚硝酸钠处理也得到了相同的结果。有趣的是，NO 增强药物在提供最大治疗优势的剂量下不会增加血浆硝酸盐水平。
这些发现表明，在 MCT 诱导的 PH 早期，NO 敏感型和非敏感型 sGC 之间的平衡并未破坏。此外，补充适量的 NO 可能是预防 PH 进展的有用治疗方法。
