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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\u2013Dawley rats were either control normoxic (Nx), or injected with Sugen 5416 (20\u2009mg\/kg, sc) and subjected to hypoxia (9% O<jats:sub>2<\/jats:sub>) (Su\u00a0+\u00a0Hx), or Su\u00a0+\u00a0Hx treated with acetazolamide (ACTZ, 100\u2009mg\/kg\/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton\u2019s 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\u2019s Index were increased in Su\u00a0+\u00a0Hx and reduced in Su\u00a0+\u00a0Hx + ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su\u00a0+\u00a0Hx and improved in Su\u00a0+\u00a0Hx + ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate\/nitrite production were reduced in pulmonary artery of Su\u00a0+\u00a0Hx and improved in Su\u00a0+\u00a0Hx + 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\u00a0+\u00a0Hx, 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\u00a0+\u00a0Hx that was ameliorated in Su\u00a0+\u00a0Hx + 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. <\/jats:p>","DOI":"10.1152\/ajpregu.00362.2020","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T17:34:20Z","timestamp":1617816860000},"page":"R835-R850","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Carbonic anhydrase inhibition improves pulmonary artery reactivity and nitric oxide-mediated relaxation in sugen-hypoxia model of pulmonary hypertension"],"prefix":"10.1152","volume":"320","author":[{"given":"Helen","family":"Christou","sequence":"first","affiliation":[{"name":"Department of Pediatric Newborn Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, 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