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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn302
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Expression and vasoconstrictor function of anorexigenic peptides neuromedin U-25 & S in the human cardiovascular system

John D. Mitchell, Janet J. Maguire, Rhoda E. Kuc and Anthony P. Davenport

Clinical Pharmacology Unit, University of Cambridge, Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, CB2 2QQ, United Kingdom

Corresponding author: John D. Mitchell Clinical Pharmacology Unit Centre for Clinical Investigation Box 110, Addenbrooke's Hospital Cambridge, CB2 2QQ, UK Tel: 01223 762564 Fax: 01223 762576 Email: jdm50{at}cam.ac.uk

Aims: Neuromedin U-25 (NMU-25), a brain-gut peptide with anorexigenic actions, was paired with the G-protein-coupled receptors NMU1 and NMU2 in 2000. NMU-25 elicited a potent hypertensive effect in rats but little is known about its cardiovascular effects in humans. We examined the hypothesis that NMU fulfils the criteria for controlling vascular reactivity within the human cardiovascular system.

Methods and Results: The radioligand [125I]-NMU-25 demonstrated specific, saturable and high affinity (KD=0.26±0.06 nM) binding in human left ventricle and coronary artery, and quantitative RT-PCR revealed that mRNA encoding NMU1 predominated in these tissues. NMU-25-like immunoreactivity was detected in human plasma, left ventricle, coronary artery, saphenous vein and epicardial adipose tissue, and both NMU-25 and a related peptide, neuromedin S (NMS), were identified by HPLC in left ventricle. NMU receptor and peptide were localised to endothelial cells, with the receptor also present on vascular smooth muscle cells. NMU-25 was a potent vasoconstrictor of isolated rings of human coronary and mammary artery and saphenous vein. Compared to NMU-25, NMS had a significantly reduced maximum response in saphenous vein, and the Arg165Trp variant of NMU-25, associated with childhood-onset obesity, was without effect. NMU-25 precursor mRNA was upregulated in left ventricle from patients with dilated cardiomyopathy and ischaemic heart disease.

Conclusion: We have detected expression of both NMU receptor and peptide in human cardiovascular tissues and have shown that NMU-25 and NMS act as potent vasoconstrictors in human vascular beds.

Time for primary review: 34 Days


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