Christou Helen, Michael Zoe, Spyropoulos Fotios, Chen Yunfei, Rong Dan, Khalil Raouf A
Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Am J Physiol Regul Integr Comp Physiol. 2021 Jun 1;320(6):R835-R850. doi: 10.1152/ajpregu.00362.2020. Epub 2021 Apr 7.
Pulmonary hypertension (PH) is a serious disease with pulmonary arterial fibrotic remodeling and limited responsiveness to vasodilators. Our data suggest that mild acidosis induced by carbonic anhydrase inhibition could ameliorate PH, but the vascular mechanisms are unclear. We tested the hypothesis that carbonic anhydrase inhibition ameliorates PH by improving pulmonary vascular reactivity and relaxation mechanisms. Male Sprague-Dawley rats were either control normoxic (Nx), or injected with Sugen 5416 (20 mg/kg, sc) and subjected to hypoxia (9% O) (Su + Hx), or Su + Hx treated with acetazolamide (ACTZ, 100 mg/kg/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton's Index; vascular function was measured in pulmonary artery, aorta, and mesenteric arteries; and pulmonary arteriolar remodeling was assessed in lung sections. Right ventricular systolic pressure and Fulton's Index were increased in Su + Hx and reduced in Su + Hx + ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su + Hx and improved in Su + Hx + ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate/nitrite production were reduced in pulmonary artery of Su + Hx and improved in Su + Hx + ACTZ. ACh relaxation was blocked by nitric oxide (NO) synthase and guanylate cyclase inhibitors, supporting a role of NO-cGMP. Sodium nitroprusside (SNP)-induced relaxation was reduced in pulmonary artery of Su + Hx, and ACTZ enhanced relaxation to SNP. Contraction/relaxation were not different in aorta or mesenteric arteries of all groups. Pulmonary arterioles showed wall thickening in Su + Hx that was ameliorated in Su + Hx + ACTZ. Thus, amelioration of pulmonary hemodynamics during carbonic anhydrase inhibition involves improved pulmonary artery reactivity and NO-mediated relaxation and may enhance responsiveness to vasodilator therapies in PH.
肺动脉高压（PH）是一种严重疾病，伴有肺动脉纤维化重塑且对血管扩张剂反应有限。我们的数据表明，碳酸酐酶抑制诱导的轻度酸中毒可改善肺动脉高压，但血管机制尚不清楚。我们检验了以下假设：碳酸酐酶抑制通过改善肺血管反应性和舒张机制来改善肺动脉高压。雄性Sprague-Dawley大鼠分为对照组常氧（Nx），或注射苏尼替尼5416（20mg/kg，皮下注射）并置于低氧环境（9%氧气）（Su + Hx），或用乙酰唑胺（ACTZ，100mg/kg/天，饮用水给药）治疗的Su + Hx组。测量血流动力学后，通过富尔顿指数评估右心室肥厚；在肺动脉、主动脉和肠系膜动脉中测量血管功能；并在肺切片中评估肺小动脉重塑。Su + Hx组右心室收缩压和富尔顿指数升高，而Su + Hx + ACTZ组降低。Su + Hx组肺动脉对氯化钾和去氧肾上腺素的收缩反应降低，而Su + Hx + ACTZ组有所改善。乙酰胆碱（ACh）诱导的舒张和硝酸盐/亚硝酸盐生成在Su + Hx组肺动脉中降低，而在Su + Hx + ACTZ组中改善。一氧化氮（NO）合酶和鸟苷酸环化酶抑制剂可阻断ACh舒张，支持NO-cGMP的作用。硝普钠（SNP）诱导的舒张在Su + Hx组肺动脉中降低，而ACTZ增强了对SNP的舒张作用。所有组的主动脉或肠系膜动脉的收缩/舒张无差异。Su + Hx组肺小动脉显示壁增厚，而Su + Hx + ACTZ组有所改善。因此，碳酸酐酶抑制期间肺血流动力学的改善涉及肺动脉反应性的改善和NO介导的舒张，并可能增强肺动脉高压对血管扩张剂治疗的反应性。
