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Neuronal Nitric Oxide Synthase Regulates Basal Microvascular Tone in Humans In Vivo
Abstract
Background— Nitric oxide (NO) has a pivotal role in the regulation of vascular tone and blood flow, with dysfunctional release contributing to disease pathophysiology. These effects have been attributed to NO production by the endothelial NO synthase (eNOS); however, recent evidence suggests that a neuronal NO synthase (nNOS) may also be expressed in arterial vessels. Methods and Results— We undertook a first-in-humans investigation of the role of nNOS in the local regulation of vascular blood flow in healthy subjects. Brachial artery infusion of the nNOS-specific inhibitor S -methyl- l -thiocitrulline (SMTC, 0.025 μmol/min to 0.2 μmol/min) caused a dose-dependent reduction in basal flow, with a 30.1±3.8% decrease at the highest dose (n=10; mean±SE; P <0.01). The effect of SMTC was abolished by coinfusion of the NO synthase substrate l -arginine but was unaffected by d -arginine. A similar reduction in basal flow with the nonselective NO synthase inhibitor N G -monomethyl- l -arginine (L-NMMA; 37.4±3.1%, n=10) required a 20-fold higher dose of 4 μmol/min. At doses that produced comparable reductions in basal flow, only L-NMMA (4 μmol/min) and not SMTC (0.2 μmol/min) inhibited acetylcholine-induced vasodilation; however, both SMTC and L-NMMA inhibited the forearm vasodilator response to mental stress. Conclusions— Basal forearm blood flow in humans is regulated by nNOS-derived NO, in contrast to the acetylcholine-stimulated increase in blood flow, which, as shown previously, is mediated primarily by eNOS. These data indicate that vascular nNOS has a distinct local role in the physiological regulation of human microvascular tone in vivo.
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“For example, l-citrulline has also been used to increase l-arginine levels (842, 1029).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [842]
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Metadata
- Authors
- Seddon, M. D., Chowienczyk, P. J., Brett, S. E., Casadei, B., & Shah, A. M.
- Affiliations
- King's College London (GB)
- From the Departments of Cardiology (M.D.S., A.M.S.) and Clinical Pharmacology (P.J.C., S.E.B.), Cardiovascular Division, King’s College London School of Medicine, London, United Kingdom; and Department of Cardiovascular Medicine (B.C.), University of Oxford, Oxford, United Kingdom.
- Venue
- Circulation
- Published
- 2008-04-15
- Volume
- 117
- Issue
- 15
- Pages
- 1991-1996
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W1982282544
- Cited by
- 129
- References
- 23
- Citations by year
- 2025: 5 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 1 · 2020: 8 · 2019: 3 · 2018: 10 · 2017: 9 · 2016: 5 · 2015: 13 · 2014: 8 · 2013: 13 · 2012: 11
- FWCI
- 6.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Abbott Laboratories
- National Institute for Health and Care Research
- British Heart Foundation (PG/05/138/20014, CVH/99001)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- neuronal nitric oxide synthase, nitric oxide, microvascular tone, S-methyl-L-thiocitrulline, L-NMMA, L-arginine, acetylcholine-induced vasodilation, endothelial nitric oxide synthase, brachial artery infusion
- MeSH terms
- Acetylcholine, Adult, Arginine, Brachial Artery, Citrulline, Forearm, Humans, Male, Nitric Oxide, Stress, Psychological, Thiourea, Vasodilation, Vasomotor System, omega-N-Methylarginine, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III
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