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


RESULTS
The radioligand [125I]-NMU-25 demonstrated specific, saturable, and high affinity (K(D) = 0.26 +/- 0.06 nM) binding in the human left ventricle and coronary artery, and quantitative reverse transcription-polymerase chain reaction 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 high-performance liquid chromatography in the left ventricle. NMU receptor and peptide were localized 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 with 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 the left ventricle from patients with dilated cardiomyopathy and ischaemic heart disease.


CONCLUSIONS
We have detected the 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.
Mitchell
John D
JD
Clinical Pharmacology Unit, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, University of Cambridge, Cambridge CB22QQ, UK. jdm50@cam.ac.uk
Maguire
Janet J
JJ
Kuc
Rhoda E
RE
Davenport
Anthony P
AP
D001345:Autoradiography; D002319:Cardiovascular System / Q000737:chemistry*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009479:Neuropeptides / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics; D011869:Radioligand Assay; D017981:Receptors, Neurotransmitter / Q000032:analysis; D014661:Vasoconstriction / Q000187:drug effects*
D009479:Neuropeptides; D011498:Protein Precursors; D017981:Receptors, Neurotransmitter; C497950:neuromedin S; C082444:neuromedin U receptor; C046271:neuromedin U 25