Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 304, Issue 9, Pages H1277-H1282Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00927.2012
Keywords
coronary blood flow; endothelial nitric oxide synthase; neuronal nitric oxide synthase; pacing; vascular
Funding
- British Heart Foundation [RE/08/003]
- Foundation Leducq Transatlantic Network of Excellence Award
- Department of Health via a National Institute for Health Research Biomedical Research Center
- King's College Hospital NHS Foundation Trust
- Academy of Medical Sciences award
- British Heart Foundation [RG/11/15/29375, FS/09/062/27958] Funding Source: researchfish
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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 mu mol/min) and L-NMMA (25 mu mol/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.
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