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Cited by 152Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionCardiovascular, Neuropeptides, and Oxidative Stress Research

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Neuronal Nitric Oxide Synthase and Human Vascular Regulation

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Melikian, Narbeh, Seddon, Michael D., Casadei, Barbara, Chowienczyk, Philip J., Shah, Ajay M.·2009·Trends in Cardiovascular Medicine
DOI 10.1016/j.tcm.2010.02.007PMC PMC2984617
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Abstract

Vascular blood flow and its distribution among different vascular beds are regulated by changes in microvascular tone. Nitric oxide (NO) plays a key role in the local paracrine regulation of vessel tone both under resting conditions and when blood flow increases in response to agonist stimulation or increased shear stress. The conventional notion that endothelial NO synthase (eNOS)-derived NO is largely responsible for both effects has been challenged by first-in-human studies with a selective inhibitor of neuronal NOS (nNOS), S-methyl-l-thiocitrulline (SMTC). These studies reveal that SMTC causes a reduction in basal blood flow in the normal human forearm and coronary circulations (that is reversed by l-arginine), without affecting the eNOS-mediated vasodilatation elicited by acetylcholine, substance P, or increased shear stress. S-methyl-l-thiocitrulline also inhibits mental stress-induced vasodilatation. These results are consistent with a significant body of experimental studies suggesting that nNOS plays an important role in the local regulation of vessel tone in other species, independent of the effects of nNOS-derived NO in the central nervous system. These emerging data suggest that eNOS and nNOS have distinct roles in the physiologic local regulation of human microvascular tone in vivo and pave the way for further detailed investigation of the relative contribution of nNOS and eNOS in vascular regulation in human disease.

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Figure 1 Effects of nNOS in the human forearm. Intraarterial infusion of the nNOS-specific inhibitor STMC into the brachial artery resulted in a dose dependent reduction in forearm blood flow (panel A). Maximal reduction in forearm blood flow in response to SMTC was abolished in the presence of excess l-arginine but not d-arginine (panel B). Intraarterial infusion of the eNOS-agonist acetylcholine (ACh) resulted in a dose-dependent increase in forearm blood flow. This response was abolished in the presence of the nonselective NOS inhibitor l-NMMA but was unaffected by SMTC. S-methyl-l-thiocitrulline had no effect on NO-independent changes in blood flow in response to intraarterial sodium nitroprusside (SNP) (panel C) (adapted from Seddon et al. 2008. Circulation 117:1991-1996).
Figure 1 Effects of nNOS in the human forearm. Intraarterial infusion of the nNOS-specific inhibitor STMC into the brachial artery resulted in a dose dependent reduction in forearm blood flow (panel A). Maximal reduction in forearm blood flow in response to SMTC was abolished in the presence of excess l-arginine but not d-arginine (panel B). Intraarterial infusion of the eNOS-agonist acetylcholine (ACh) resulted in a dose-dependent increase in forearm blood flow. This response was abolished in the presence of the nonselective NOS inhibitor l-NMMA but was unaffected by SMTC. S-methyl-l-thiocitrulline had no effect on NO-independent changes in blood flow in response to intraarterial sodium nitroprusside (SNP) (panel C) (adapted from Seddon et al. 2008. Circulation 117:1991-1996).CC BY · PubMed Central
Figure 2 Effects of nNOS in the human coronary circulation. Intracoronary Doppler ultrasound traces demonstrating average peak velocity (APV) values at baseline and after infusion of the endothelial agonist substance P. Volumetric coronary blood flow can be obtained from the product of APV values and the cross-sectional area of the coronary vessel (calculated from measuring the diameter of the epicardial vessel with the use of quantitative coronary angiography [QCA]) at the time of APV recording (panel A). Doppler/QCA was used to derive changes in coronary blood flow in response to the nNOS-selective inhibitor SMTC and the nonselective NOS inhibitor l-NMMA during cardiac catheterization in patients who turned out to have unobstructed/smooth coronary vessels. As in the forearm, intracoronary infusion of the SMTC reduced coronary blood flow. This response was abolished in the presence of excess l-arginine but not d-arginine (panel B). Intracoronary infusion of the eNOS-agonist substance P increased coronary blood flow. This response was abolished in the presence of l-NMMA but was unaffected by SMTC (panel C) (adapted from Seddon et al. 2009. Circulation 119:2656-2662).
Figure 2 Effects of nNOS in the human coronary circulation. Intracoronary Doppler ultrasound traces demonstrating average peak velocity (APV) values at baseline and after infusion of the endothelial agonist substance P. Volumetric coronary blood flow can be obtained from the product of APV values and the cross-sectional area of the coronary vessel (calculated from measuring the diameter of the epicardial vessel with the use of quantitative coronary angiography [QCA]) at the time of APV recording (panel A). Doppler/QCA was used to derive changes in coronary blood flow in response to the nNOS-selective inhibitor SMTC and the nonselective NOS inhibitor l-NMMA during cardiac catheterization in patients who turned out to have unobstructed/smooth coronary vessels. As in the forearm, intracoronary infusion of the SMTC reduced coronary blood flow. This response was abolished in the presence of excess l-arginine but not d-arginine (panel B). Intracoronary infusion of the eNOS-agonist substance P increased coronary blood flow. This response was abolished in the presence of l-NMMA but was unaffected by SMTC (panel C) (adapted from Seddon et al. 2009. Circulation 119:2656-2662).CC BY · PubMed Central
Figure 3 Potential in vivo sources of nNOS-derived NO. Schematic representation of the potential sources of nNOS and nNOS-derived NO in vivo. Neuronal NOS is known to be expressed in endothelial and smooth muscle cells within the vascular wall as well as skeletal muscle cells and perivascular nerve fibers. The nNOS-derived NO from one or more of these sources may influence vascular tone.
Figure 3 Potential in vivo sources of nNOS-derived NO. Schematic representation of the potential sources of nNOS and nNOS-derived NO in vivo. Neuronal NOS is known to be expressed in endothelial and smooth muscle cells within the vascular wall as well as skeletal muscle cells and perivascular nerve fibers. The nNOS-derived NO from one or more of these sources may influence vascular tone.CC BY · PubMed Central

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Metadata

Authors
Melikian, N., Seddon, M. D., Casadei, B., Chowienczyk, P. J., & Shah, A. M.
Affiliations
  • King's College London (GB)
  • University of Oxford (GB)
Corresponding author
Shah, Ajay M.
ORCID
Venue
Trends in Cardiovascular Medicine
Publisher
Elsevier BV
Published
2009-11
Volume
19
Issue
8
Pages
256-262
ISSN
1050-1738 (ISSN-L)
DOI
10.1016/j.tcm.2010.02.007
PMC
PMC2984617
OpenAlex
W2095106948
Cited by
151
References
43
Citations by year
2026: 1 · 2025: 8 · 2024: 5 · 2023: 16 · 2022: 8 · 2021: 4 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 11 · 2016: 6 · 2015: 11 · 2014: 15 · 2013: 13 · 2012: 15
FWCI
1.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Cardiovascular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
  • King's College Hospital NHS Foundation Trust
  • National Institute for Health and Care Research
  • British Heart Foundation (FS/09/062/27958)
  • King's College London
Topics
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
Keywords
neuronal nitric oxide synthase, endothelial nitric oxide synthase, nitric oxide, microvascular tone, S-methyl-L-thiocitrulline, L-arginine, shear stress, acetylcholine, substance P, coronary circulation, forearm blood flow, paracrine regulation
MeSH terms
Animals, Citrulline, Coronary Vessels, Enzyme Inhibitors, Forearm, Humans, Microcirculation, Nitric Oxide, Stress, Psychological, Thiourea, Vasodilation, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III, Microvessels

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