Neuronal nitric oxide synthase and human vascular regulation.
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.
Melikian
Narbeh
N
King's College London British Heart Foundation Centre of Excellence, Cardiovascular Division, London, United Kingdom.
Seddon
Michael D
MD
Casadei
Barbara
B
Chowienczyk
Philip J
PJ
Shah
Ajay M
AM
D000818:Animals; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000201:enzymology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D002956:Citrulline; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496314:NOS3 protein, human; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D013890:Thiourea; C086717:S-methylthiocitrulline
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