{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:07:42Z","timestamp":1790676462593,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014461","name":"National Institute for Health Research Biomedical Research Centre","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014461","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guy\u2019s & St Thomas\u2019 NHS Foundation Trust and King\u2019s College London","award":["IS-BRC-1215-20006"],"award-info":[{"award-number":["IS-BRC-1215-20006"]}]},{"name":"NIHR SLaM Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King\u2019s College London","award":["IS-BRC-1215-20018"],"award-info":[{"award-number":["IS-BRC-1215-20018"]}]},{"name":"King\u2019s College Hospital NHS Foundation Trust. We also acknowledge support from the British Heart Foundation","award":["CH\/1999001\/11735"],"award-info":[{"award-number":["CH\/1999001\/11735"]}]},{"name":"King\u2019s College Hospital NHS Foundation Trust. We also acknowledge support from the British Heart Foundation","award":["RE\/18\/2\/34213"],"award-info":[{"award-number":["RE\/18\/2\/34213"]}]},{"name":"UK Medical Research Council Clinical Research Training Fellowship","award":["MR\/R017751\/1"],"award-info":[{"award-number":["MR\/R017751\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Neuronal nitric oxide synthase (nNOS) is highly expressed within the cardiovascular and nervous systems. Studies in genetically modified mice suggest roles in brain blood flow regulation while dysfunctional nNOS signalling is implicated in cerebrovascular ischaemia and migraine. Previous human studies have investigated the effects of non-selective NOS inhibition but there has been no direct investigation of the role of nNOS in human cerebrovascular regulation. We hypothesized that inhibition of the tonic effects of nNOS would result in global or localized changes in cerebral blood flow (CBF), as well as changes in functional brain connectivity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We investigated the acute effects of a selective nNOS inhibitor, S-methyl-L-thiocitrulline (SMTC), on CBF and brain functional connectivity in healthy human volunteers (n\u2009=\u200919). We performed a randomized, placebo-controlled, crossover study with either intravenous SMTC or placebo, using magnetic resonance imaging protocols with arterial spin labelling and functional resting state neuroimaging. SMTC infusion induced an \u223c4% decrease in resting global CBF [\u22122.3 (\u22120.3, \u22124.2) mL\/100g\/min, mean (95% confidence interval, CI), P\u2009=\u20090.02]. In a whole-brain voxel-wise factorial-design comparison of CBF maps, we identified a localized decrease in regional blood flow in the right hippocampus and parahippocampal gyrus following SMTC vs. placebo (2921 voxels; T\u2009=\u20097.0; x\u2009=\u200936; y = \u221232; z = \u221212; P\u2009&amp;lt;\u20090.001). This was accompanied by a decrease in functional connectivity to the left superior parietal lobule vs. placebo (484 voxels; T\u2009=\u20095.02; x = \u221214; y = \u221256; z\u2009=\u200974; P\u2009=\u20090.009). These analyses adjusted for the modest changes in mean arterial blood pressure induced by SMTC as compared to placebo [+8.7\u2009mmHg (+1.8, +15.6), mean (95% CI), P\u2009=\u20090.009].<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These data suggest a fundamental physiological role of nNOS in regulating regional CBF and functional connectivity in the human hippocampus. Our findings have relevance to the role of nNOS in the regulation of cerebral perfusion in health and disease.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvab155","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T19:36:14Z","timestamp":1619638574000},"page":"1321-1329","source":"Crossref","is-referenced-by-count":38,"title":["Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans"],"prefix":"10.1093","volume":"118","author":[{"given":"Kevin","family":"O\u2019Gallagher","sequence":"first","affiliation":[{"name":"Department of Cardiology, King\u2019s College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK"},{"name":"Department of Clinical Pharmacology, King\u2019s College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1933-4049","authenticated-orcid":false,"given":"Francesca","family":"Puledda","sequence":"additional","affiliation":[{"name":"Headache Group, Wolfson CARD, Institute of Psychology, Psychiatry and Neuroscience, London, UK"},{"name":"NIHR-Wellcome Trust King's Clinical Research Facility, SLaM Biomedical Research Centre, King's College Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"O\u2019Daly","sequence":"additional","affiliation":[{"name":"Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-195X","authenticated-orcid":false,"given":"Matthew","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, King\u2019s College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Dancy","sequence":"additional","affiliation":[{"name":"Department of Cardiology, King\u2019s College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J","family":"Chowienczyk","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, King\u2019s College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Zelaya","sequence":"additional","affiliation":[{"name":"Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3260-5904","authenticated-orcid":false,"given":"Peter J","family":"Goadsby","sequence":"additional","affiliation":[{"name":"Headache Group, Wolfson CARD, Institute of Psychology, Psychiatry and Neuroscience, London, UK"},{"name":"NIHR-Wellcome Trust King's Clinical Research Facility, SLaM Biomedical Research Centre, King's College Hospital, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6547-0631","authenticated-orcid":false,"given":"Ajay M","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Cardiology, King\u2019s College London British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine & Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, 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