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(Circulation. 2008;117:1991-1996.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Neuronal Nitric Oxide Synthase Regulates Basal Microvascular Tone in Humans In Vivo

Michael D. Seddon, MRCP; Philip J. Chowienczyk, FRCP; Sally E. Brett, PhD; Barbara Casadei, MD, FRCP; Ajay M. Shah, MD, FRCP

From the Departments of Cardiology (M.D.S., A.M.S.) and Clinical Pharmacology (P.J.C., S.E.B.), Cardiovascular Division, King’s College London School of Medicine, London, United Kingdom; and Department of Cardiovascular Medicine (B.C.), University of Oxford, Oxford, United Kingdom.

Correspondence to Professor Ajay M. Shah, Department of Cardiology, The James Black Centre, King’s College London School of Medicine, 125 Coldharbour Ln, London SE5 9NU, United Kingdom. E-mail ajay.shah{at}kcl.ac.uk

Received October 6, 2007; accepted February 18, 2008.

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 N^G-monomethyl-L-arginine (L-NMMA; 37.4±3.1%, n=10) required a 20-fold higher dose of 4 µmol/min. At doses that produced comparable reductions in basal flow, only L-NMMA (4 µmol/min) and not SMTC (0.2 µmol/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.

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CLINICAL PERSPECTIVE

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