Neuronal nitric oxide synthase regulates regional brain perfusion in healthy humans

Abstract Aims 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. Previo...

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Bibliographic Details
Published in:Cardiovascular research 2022-03, Vol.118 (5), p.1321-1329
Main Authors: O’Gallagher, Kevin, Puledda, Francesca, O’Daly, Owen, Ryan, Matthew, Dancy, Luke, Chowienczyk, Philip J, Zelaya, Fernando, Goadsby, Peter J, Shah, Ajay M
Format: Article
Language:English
Subjects:
Animals
Brain - metabolism
Cross-Over Studies
Enzyme Inhibitors - pharmacology
Humans
Mice
Nitric Oxide
Nitric Oxide Synthase Type I - metabolism
Original
Perfusion
Regional Blood Flow
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Summary:Abstract Aims 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. Methods and results 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 = 19). 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 ∼4% decrease in resting global CBF [−2.3 (−0.3, −4.2) mL/100g/min, mean (95% confidence interval, CI), P = 0.02]. 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 = 7.0; x = 36; y = −32; z = −12; P 
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvab155