This Article Full Text Full Text (PDF) All Versions of this Article: 119/20/2656    most recent CIRCULATIONAHA.108.822205v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Seddon, M. Articles by Shah, A. M. Search for Related Content PubMed PubMed Citation Articles by Seddon, M. Articles by Shah, A. M. Related Collections Coronary circulation Endothelium/vascular type/nitric oxide

(Circulation. 2009;119:2656-2662.)
© 2009 American Heart Association, Inc.

Coronary Heart Disease

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

Michael Seddon, MD, MRCP; Narbeh Melikian, MRCP; Rafal Dworakowski, MD, PhD; Husain Shabeeh, MRCP; Benyu Jiang, PhD; Jonathan Byrne, PhD, MRCP; Barbara Casadei, MD, DPhil; Philip Chowienczyk, FRCP; Ajay M. Shah, MD, FMedSci

From King’s College London British Heart Foundation Centre, Cardiovascular Division, Departments of Cardiology (M.S., N.M., R.D., H.S., J.B., A.M.S.) and Clinical Pharmacology (B.J., P.C.), London, and Department of Cardiovascular Medicine, University of Oxford, Oxford (B.C.), UK.

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, UK. E-mail ajay.shah{at}kcl.ac.uk

Received September 16, 2008; accepted April 1, 2009.

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 µmol/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 µmol/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 µmol/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 µmol/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 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.

---

 

CLINICAL PERSPECTIVE