Neuronal nitric oxide synthase regulates basal microvascular tone in humans in vivo.
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.


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 micromol/min to 0.2 micromol/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 micromol/min. At doses that produced comparable reductions in basal flow, only L-NMMA (4 micromol/min) and not SMTC (0.2 micromol/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.
Seddon
Michael D
MD
Department of Cardiology, King's College London School of Medicine, 125 Coldharbour Ln, London SE5 9NU, United Kingdom.
Chowienczyk
Philip J
PJ
Brett
Sally E
SE
Casadei
Barbara
B
Shah
Ajay M
AM
D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology; D000328:Adult; D001120:Arginine / Q000494:pharmacology; D001916:Brachial Artery / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019323:omega-N-Methylarginine; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; 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; D000109:Acetylcholine