{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:14:58Z","timestamp":1789154098412,"version":"build-2803163510"},"reference-count":70,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T00:00:00Z","timestamp":1737763200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T00:00:00Z","timestamp":1737763200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2025,7]]},"abstract":"\n To what extent sildenafil, a selective inhibitor of the type-5 phosphodiesterase modulates systemic redox status and cerebrovascular function during acute exposure to hypoxia remains unknown. To address this, 12 healthy males (aged 24\u2009\u00b1\u20093\u2009y) participated in a randomized, placebo-controlled crossover study involving exposure to both normoxia and acute (60\u2009min) hypoxia (Fi\n \n \n \n \n O<\/mml:mtext>\n <\/mml:mrow>\n \n 2<\/mml:mn>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:inline-formula>\n \u2009=\u20090.14), followed by oral administration of 50\u2009mg sildenafil and placebo (double-blinded). Venous blood was sampled for the ascorbate radical (A\n \u2022\u2212<\/jats:sup>\n : electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (NO: ozone-based chemiluminescence). Transcranial Doppler ultrasound was employed to determine middle cerebral artery velocity (MCAv), cerebral delivery of oxygen\n \n \n \n \n (CDO<\/mml:mtext>\n <\/mml:mrow>\n \n 2<\/mml:mn>\n <\/mml:mrow>\n <\/mml:msub>\n ),<\/mml:mtext>\n <\/mml:math>\n <\/jats:inline-formula>\n dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to hypo\/hypercapnia (CVR\n CO2HYPO\/HYPER<\/jats:sub>\n ). Cortical oxyhemoglobin (cO\n 2<\/jats:sub>\n Hb) and oxygenation index (OI) were assessed using pulsed continuous wave near infra-red spectroscopy. Hypoxia decreased total plasma NO (\n P\u2009=\u2009<\/jats:italic>\n 0.008),\n \n \n \n \n CDO<\/mml:mtext>\n <\/mml:mrow>\n \n 2<\/mml:mn>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:math>\n <\/jats:inline-formula>\n (\n P<\/jats:italic>\n \u2009=\u2009<0.001) and cO\n 2<\/jats:sub>\n Hb (\n P\u2009=\u2009<\/jats:italic>\n 0.005). In hypoxia, sildenafil selectively reduced A\n \u2022\u2212<\/jats:sup>\n (\n P\u2009=\u2009<\/jats:italic>\n 0.018) and MCA\n V<\/jats:sub>\n (\n P\u2009=\u2009<\/jats:italic>\n 0.018), and increased dCA metrics of low-frequency phase (\n P\u2009=\u2009<\/jats:italic>\n 0.029) and CVR\n CO2HYPER<\/jats:sub>\n (\n P\u2009=\u2009<\/jats:italic>\n 0.007) compared to hypoxia-placebo. Collectively, these findings provide evidence for a PDE-5 inhibitory pathway that enhances select aspects of cerebrovascular function in hypoxia subsequent to a systemic improvement in redox homeostasis and independent of altered vascular NO bioavailability.\n <\/jats:p>","DOI":"10.1177\/0271678x251313747","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T12:28:07Z","timestamp":1738153687000},"page":"1343-1356","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Phosphodiesterase inhibition restores hypoxia-induced cerebrovascular dysfunction subsequent to improved systemic redox homeostasis: A randomized, double-blind, placebo-controlled crossover study"],"prefix":"10.1177","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1005-7038","authenticated-orcid":false,"given":"Benjamin S","family":"Stacey","sequence":"first","affiliation":[{"name":"University of 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