{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:03:41Z","timestamp":1790676221559,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2020,8,31]],"date-time":"2020-08-31T00:00:00Z","timestamp":1598832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","award":["G\u201018\u20100022304"],"award-info":[{"award-number":["G\u201018\u20100022304"]}],"id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Preclinical models have demonstrated that nitric oxide is a key component of neurovascular coupling; this has yet to be translated to humans.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conducted two separate protocols utilizing intravenous infusion of a nitric oxide synthase inhibitor and isovolumic haemodilution to assess the influence of nitric oxide on neurovascular coupling in humans.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Isovolumic haemodilution did not alter neurovascular coupling.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Intravenous infusion of a nitric oxide synthase inhibitor reduced the neurovascular coupling response by \u223c30%, indicating that nitric oxide is integral to neurovascular coupling in humans.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Nitric oxide is a vital neurovascular signalling molecule in preclinical models, yet the mechanisms underlying neurovascular coupling (NVC) in humans have yet to be elucidated. To investigate the contribution of nitric oxide to NVC in humans, we utilized a visual stimulus paradigm to elicit an NVC response in the posterior cerebral circulation. Two distinct mechanistic interventions were conducted on young healthy males: (1) NVC was assessed during intravenous infusion of saline (placebo) and the non\u2010selective competitive nitric oxide synthase inhibitor <jats:italic>N<\/jats:italic><jats:sup>G<\/jats:sup>\u2010monomethyl\u2010<jats:sc>l<\/jats:sc>\u2010arginine (<jats:sc>l<\/jats:sc>\u2010NMMA, 5\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup> bolus &amp; subsequent 50\u00a0\u03bcg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0min<jats:sup>\u22121<\/jats:sup> maintenance dose; <jats:italic>n<\/jats:italic>\u00a0=\u00a010). The order of infusion was randomized, counterbalanced and single blinded. A subset of participants in this study (<jats:italic>n<\/jats:italic>\u00a0=\u00a04) underwent a separate intervention with phenylephrine infusion to independently consider the influence of blood pressure changes on NVC (0.1\u20130.6\u00a0\u03bcg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0min<jats:sup>\u22121<\/jats:sup> constant infusion). (2) NVC was assessed prior to and following isovolumic haemodilution, whereby 20% of whole blood was removed and replaced with 5% human serum albumin to reduce haemoglobin concentration (<jats:italic>n<\/jats:italic>\u00a0=\u00a08). For both protocols, arterial and internal jugular venous blood samples were collected at rest and coupled with volumetric measures of cerebral blood flow (duplex ultrasound) to quantify resting cerebral metabolic parameters. <jats:sc>l<\/jats:sc>\u2010NMMA elicited a 30% reduction in the peak (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.01), but not average (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.11), NVC response. Neither phenylephrine nor haemodilution influenced NVC. Nitric oxide signalling is integral to NVC in humans, providing a new direction for research into pharmacological treatment of humans with dementia.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp280162","type":"journal-article","created":{"date-parts":[[2020,8,12]],"date-time":"2020-08-12T14:07:44Z","timestamp":1597241264000},"page":"4927-4939","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Nitric oxide is fundamental to neurovascular coupling in humans"],"prefix":"10.1113","volume":"598","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-0059","authenticated-orcid":false,"given":"Ryan L.","family":"Hoiland","sequence":"first","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences University of British Columbia Okanagan  Kelowna BC V1V 1V7 Canada"},{"name":"Department of Anesthesiology, Pharmacology, and Therapeutics Vancouver General Hospital  899 West 12th Avenue Vancouver BC V5Z 1M9 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6072-7277","authenticated-orcid":false,"given":"Hannah G.","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences University of British Columbia Okanagan  Kelowna BC V1V 1V7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1133-2444","authenticated-orcid":false,"given":"Connor A.","family":"Howe","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences University of British Columbia Okanagan  Kelowna BC V1V 1V7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Nowak\u2010Fl\u00fcck","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health, School of Health and Exercise Sciences University of British Columbia Okanagan  Kelowna BC V1V 1V7 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin S.","family":"Stacey","sequence":"additional","affiliation":[{"name":"Neurovascular Research Laboratory, Faculty of Life Sciences and Education University of South Wales  Pontypridd CF37 4BB UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-7095","authenticated-orcid":false,"given":"Damian M.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Neurovascular Research Laboratory, Faculty of Life Sciences and Education University of South Wales  Pontypridd CF37 4BB UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7410-2913","authenticated-orcid":false,"given":"Julian F. R.","family":"Paton","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medical &amp; Health Sciences University of Auckland  Park Road Grafton Auckland 1142 New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3226-2921","authenticated-orcid":false,"given":"Daniel J.","family":"Green","sequence":"additional","affiliation":[{"name":"School of Human Sciences (Exercise and Sport Sciences) The University of Western Australia  Nedlands Western Australia 6009 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mypinder S.","family":"Sekhon","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Department of Medicine, Vancouver General Hospital, West 12th Avenue University of British Columbia  Vancouver BC V5Z 1M9 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