{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:51:32Z","timestamp":1791222692281,"version":"4.1.0"},"reference-count":68,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T00:00:00Z","timestamp":1640822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000383","name":"Higher Education Funding Council for Wales","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000383","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":[[2022,3]]},"abstract":"\n Abstract<\/jats:title>\n \n Cerebrovascular CO\n 2<\/jats:sub>\n reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear\u2010mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)\u2010dependency of CVR and cSMD. Eleven volunteers underwent a steady\u2010state CVR test and transient CO\n 2<\/jats:sub>\n test of cSMD during intravenous infusion of the NO synthase inhibitor\n N<\/jats:italic>\n G<\/jats:sup>\n \u2010monomethyl\u2010\n l<\/jats:sc>\n \u2010arginine (\n l<\/jats:sc>\n \u2010NMMA) or volume\u2010matched saline (placebo; single\u2010blinded and counter\u2010balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra\u2010arterial blood pressure and\n \n . Paired arterial and jugular venous blood sampling allowed for the determination of trans\u2010cerebral NO\n 2<\/jats:sub>\n \u2212<\/jats:sup>\n exchange (ozone\u2010based chemiluminescence).\n l<\/jats:sc>\n \u2010NMMA reduced arterial NO\n 2<\/jats:sub>\n \u2212<\/jats:sup>\n by \u223c25%\n versus<\/jats:italic>\n saline (74.3\u00a0\u00b1\u00a039.9\n vs<\/jats:italic>\n . 98.1\u00a0\u00b1\u00a034.2\u00a0nM;\n P<\/jats:italic>\n \u00a0=\u00a00.03). The steady\u2010state CVR (20.1\u00a0\u00b1\u00a011.6\u00a0nM\/min at baseline\n vs<\/jats:italic>\n . 3.2\u00a0\u00b1\u00a016.7\u00a0nM\/min at +9 mmHg\n \n ;\n P<\/jats:italic>\n \u00a0=\u00a00.017) and transient cSMD tests (3.4\u00a0\u00b1\u00a05.9\u00a0nM\/min at baseline\n vs<\/jats:italic>\n . \u22121.8\u00a0\u00b1\u00a08.2\u00a0nM\/min at 120 s post\u2010CO\n 2<\/jats:sub>\n ;\n P<\/jats:italic>\n \u00a0=\u00a00.044) shifted trans\u2010cerebral NO\n 2<\/jats:sub>\n \u2212<\/jats:sup>\n exchange towards a greater net release (a negative value indicates release). Although this trans\u2010cerebral NO\n 2<\/jats:sub>\n \u2212<\/jats:sup>\n release was abolished by\n l<\/jats:sc>\n \u2010NMMA, CVR did not differ between the saline and\n l<\/jats:sc>\n \u2010NMMA trials (57.2\u00a0\u00b1\u00a014.6\n vs<\/jats:italic>\n . 54.1\u00a0\u00b1\u00a012.1\u00a0ml\/min\/mmHg;\n P<\/jats:italic>\n \u00a0=\u00a00.49), nor did\n l<\/jats:sc>\n \u2010NMMA impact peak internal carotid artery dilatation during the steady\u2010state CVR test (6.2\u00a0\u00b1\u00a04.5\n vs<\/jats:italic>\n . 6.2\u00a0\u00b1\u00a05.0% dilatation;\n P<\/jats:italic>\n \u00a0=\u00a00.960). However,\n l<\/jats:sc>\n \u2010NMMA reduced cSMD by \u223c37% compared to saline (2.91\u00a0\u00b1\u00a01.38\n vs<\/jats:italic>\n . 4.65\u00a0\u00b1\u00a02.50%;\n P<\/jats:italic>\n \u00a0=\u00a00.009). Our findings indicate that NO is not an obligatory regulator of steady\u2010state CVR. Further, our novel transient CO\n 2<\/jats:sub>\n test of cSMD is largely NO\u2010dependent and provides an\n in vivo<\/jats:italic>\n bioassay of NO\u2010mediated cerebrovascular function in humans.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Emerging evidence indicates that a transient CO\n 2<\/jats:sub>\n stimulus elicits shear\u2010mediated dilatation of the internal carotid artery, termed cerebral shear\u2010mediated dilatation.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Whether or not cerebrovascular reactivity to a steady\u2010state CO\n 2<\/jats:sub>\n stimulus is NO\u2010dependent remains unclear in humans.\n <\/jats:p>\n <\/jats:list-item>\n \n \n During both a steady\u2010state cerebrovascular reactivity test and a transient CO\n 2<\/jats:sub>\n test of cerebral shear\u2010mediated dilatation, trans\u2010cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non\u2010selective NO synthase inhibitor\n N<\/jats:italic>\n G<\/jats:sup>\n \u2010monomethyl\u2010\n l<\/jats:sc>\n \u2010arginine.\n <\/jats:p>\n <\/jats:list-item>\n \n \n NO synthase blockade did not alter cerebrovascular reactivity in the steady\u2010state CO\n 2<\/jats:sub>\n test; however, cerebral shear\u2010mediated dilatation following a transient CO\n 2<\/jats:sub>\n stimulus was reduced by \u223c37% following intravenous infusion of\n N<\/jats:italic>\n G<\/jats:sup>\n \u2010monomethyl\u2010\n l<\/jats:sc>\n \u2010arginine.\n <\/jats:p>\n <\/jats:list-item>\n \n \n NO is not obligatory for cerebrovascular reactivity to CO\n 2<\/jats:sub>\n , but is a key contributor to cerebral shear\u2010mediated dilatation.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp282427","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T21:04:52Z","timestamp":1639429492000},"page":"1385-1403","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Nitric oxide contributes to cerebrovascular shear\u2010mediated dilatation but not steady\u2010state cerebrovascular reactivity to carbon dioxide"],"prefix":"10.1113","volume":"600","author":[{"given":"Ryan L.","family":"Hoiland","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Pharmacology and Therapeutics Faculty of Medicine Vancouver General Hospital University of British Columbia Vancouver British Columbia Canada"},{"name":"Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Sciences University of British Columbia Okanagan Kelowna British Columbia Canada"},{"name":"Department of Cellular and Physiological Sciences Faculty of Medicine University of British Columbia Vancouver British Columbia Canada"},{"name":"International Collaboration on Repair Discoveries (ICORD) University of British Columbia Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7236-1348","authenticated-orcid":false,"given":"Jay M. 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