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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 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.

Original publication

DOI

10.1161/CIRCULATIONAHA.107.744540

Type

Journal article

Journal

Circulation

Publication Date

15/04/2008

Volume

117

Pages

1991 - 1996

Keywords

Acetylcholine, Adult, Arginine, Brachial Artery, Citrulline, Forearm, Humans, Male, Nitric Oxide, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III, Stress, Psychological, Thiourea, Vasodilation, Vasomotor System, omega-N-Methylarginine