title: Differential role of endothelial versus neuronal nitric oxide synthase in the regulation of coronary blood flow during pacing-induced increases in cardiac workload.
abstract: Endothelial nitric oxide synthase (eNOS) was assumed to be the only source of nitric oxide (NO) involved in the regulation of human coronary blood flow (CBF). However, our recent first-in-human study using the neuronal NOS (nNOS)-selective inhibitor S-methyl-L-thiocitrulline (SMTC) showed that nNOS-derived NO also plays a role. In this study, we investigated the relative contribution of nNOS and eNOS to the CBF response to a pacing-induced increase in cardiac workload. Incremental right atrial pacing was undertaken in patients with angiographically normal coronary arteries during intracoronary infusion of saline vehicle and then either SMTC or N(G)-monomethyl-l-arginine (l-NMMA; which inhibits both eNOS and nNOS). Intracoronary SMTC (0.625 μmol/min) and l-NMMA (25 μmol/min) reduced basal CBF to a similar extent (-19.2 ± 3.2% and 25.0 ± 2.7%, respectively; n = 10 per group). Pacing-induced increases in CBF were significantly blunted by l-NMMA (maximum CBF: 83.5 ± 14.2 ml/min during saline vs. 61.6 ± 9.5 ml/min during l-NMMA; P < 0.01). By contrast, intracoronary SMTC had no effect on the maximum CBF during pacing (98.5 ± 12.9 ml/min during saline vs. 102.1 ± 16.6 ml/min during SMTC; P = not significant). l-NMMA also blunted the pacing-induced increase in coronary artery diameter (P < 0.001 vs. saline), whereas SMTC had no effect. Our results confirm a role of nNOS in the regulation of basal CBF in humans but show that coronary vasodilation in response to a pacing-induced increase in cardiac workload is exclusively mediated by eNOS-derived NO.
authors.affiliation: King's College London British Heart Foundation Centre, Cardiovascular Division, London, United Kingdom.
authors.forename: Husain
authors.initials: H
authors.lastname: Shabeeh
authors.forename: Narbeh
authors.initials: N
authors.lastname: Melikian
authors.forename: Rafal
authors.initials: R
authors.lastname: Dworakowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Casadei
authors.forename: Phil
authors.initials: P
authors.lastname: Chowienczyk
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
mesh_terms: D001794:Blood Pressure / Q000187:drug effects; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D019323:omega-N-Methylarginine; D002956:Citrulline; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D013890:Thiourea; C086717:S-methylthiocitrulline
keywords: coronary blood flow; endothelial nitric oxide synthase; neuronal nitric oxide synthase; pacing; vascular