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.


RESULTS
In patients with angiographically normal coronary arteries, intracoronary infusion of SMTC (0.625 micromol/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 micromol/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 micromol/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 micromol/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 approximately 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.
King's College London British Heart Foundation Centre, Cardiovascular Division, Department of Cardiology, London, UK.
Michael
M
Seddon
Narbeh
N
Melikian
Rafal
R
Dworakowski
Husain
H
Shabeeh
Benyu
B
Jiang
Jonathan
J
Byrne
Barbara
B
Casadei
Philip
P
Chowienczyk
Ajay M
AM
Shah
D000328:Adult; D002956:Citrulline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D003331:Coronary Vessels / Q000502:physiology*; 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; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000502:physiology; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D055815:Young Adult
D002956:Citrulline; D009569:Nitric Oxide; D013373:Substance P; 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