Effects of Neuronal Nitric Oxide Synthase on Human Coronary Artery Diameter and Blood Flow In Vivo

Background-Nitric oxide (NO)-mediated local regulation of vascular tone is considered to involve endothelial NO synthase ( eNOS). However, we recently reported that human forearm basal microvascular tone in vivo is tonically regulated by neuronal NO synthase ( nNOS), in contrast to an acetylcholine-stimulated reduction in tone, which is eNOS dependent. Here, we investigated the in vivo effects of an nNOS-selective inhibitor, S-methyl-L-thiocitrulline (SMTC), on the human coronary circulation and on flow-mediated dilatation in the forearm. Methods and Results-In patients with angiographically normal coronary arteries, intracoronary infusion of SMTC (0.625 mu mol/min) reduced basal coronary blood flow by 34.1 +/- 5.2% (n=10; P<0.01) and epicardial coronary diameter by 3.6 +/- 1.2% (P=0.02) but had no effect on increases in flow evoked by intracoronary substance P (20 pmol/min). The nonselective NOS inhibitor N-G-monomethyl-L-arginine (25 mu mol/min) also reduced basal coronary flow (by 22.3 +/- 5.3%; n=8; P<0.01) but, in contrast to SMTC, inhibited substance P-induced increases in flow (P<0.01). In healthy volunteers, local infusion of SMTC (0.2 mu mol/min) reduced radial artery blood flow by 36.0 +/- 6.4% (n=10; P=0.03) but did not affect flow-mediated dilatation (P=0.55). In contrast, N-G-monomethyl-L-arginine (2 mu mol/min) infusion reduced radial blood flow to a similar degree (by 39.7 +/- 11.8%; P=0.02) but also inhibited flow-mediated dilatation by approximate to 80% (P<0.01). Conclusions-These data indicate that local nNOS-derived NO regulates basal blood flow in the human coronary vascular bed, whereas substance P-stimulated vasodilatation is eNOS mediated. Thus, nNOS and eNOS have distinct local roles in the physiological regulation of human coronary vascular tone in vivo. (Circulation. 2009; 119: 2656-2662.)