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. 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 NG-monomethyl-l-arginine (L-NMMA; 37.4±3.1%, n=10) requ...