Brain-gut peptide neuromedin U-25 is a novel transmitter in the human cardiovascular system

John Mitchell, Janet Maguire, Rhoda Kuc, Anthony Davenport

University of Cambridge, Cambridge, UK

Neuromedin U (NMU), discovered in porcine spinal cord and named for its ability to contract rat uterus (Minamino et al., 1985), was paired with the previously designated ‘orphan’ G-protein-coupled receptors, NMU1 and NMU2 (Howard et al., 2000). More recently, a structurally related peptide, neuromedin S (NMS), was isolated from rat brain and found to act at the same receptors (Mori et al., 2005). Research has focused on the role of NMU in regulation of energy balance (Howard et al., 2000), reflecting its brain-gut distribution (Szekeres et al., 2000). An amino-acid variant (Arg165Trp) of NMU-25 is associated with childhood-onset obesity (Hainerova et al., 2007). Initial studies showed both peptides elicit potent pressor responses in rats (Minamino et al., 1985; Mori et al., 2005); however, little is known about the direct effect of NMU on blood vessels and, in particular, on its vascular effects in humans.

Using the radioligand [125I]-NMU-25, we characterised receptors in human left ventricle (LV) and coronary artery (CA) based on the pharmacological criteria of specific, saturable and high affinity binding (KD = 0.26 ± 0.06 nM, n=4). Quantitative RT-PCR subsequently demonstrated that mRNA encoding NMU1 was predominant in human cardiovascular tissues. The specificity of anti-human NMU1 antiserum was verified by Western blotting and NMU1 was localised to vascular endothelial and smooth muscle cells using dual-labelling fluorescent immunohistochemistry. Levels of NMU-25-like immunoreactivity were measured using a novel radioimmunoassay in human plasma (3.7 ± 0.7 pM, n=4), LV, CA, saphenous vein (SV) and epicardial adipose tissue. This assay was 100% cross-reactive for NMU-25 and NMS; reverse phase-high performance liquid chromatography enabled identification of both peptides in LV. Immunoreactive peptide co-localised with von Willebrand factor, suggesting an endothelial source. Most importantly, we report a potent vasoconstrictor function for NMU-25 in human CA (pD2, 8.6 ± 0.1; EC50, 32.1 ± 10.8; n=8) and SV (pD2, 8.2 ± 0.1; EC50, 38.4 ± 2.6; n=65), dependent on an intracellular source of calcium. NMS potently constricted SV but had a significantly lower maximum response compared to NMU-25 while the Arg165Trp variant of NMU-25 was without effect. Intriguingly, NMU-25 precursor mRNA was upregulated in LV from patients with dilated cardiomyopathy and ischaemic heart disease.

In conclusion, we have shown the presence of specific NMU receptors and their cognate ligands, NMU-25 and NMS, in the human cardiovascular system. Furthermore, we have characterised a potent vasoconstrictor function for NMU-25 in human artery and vein. Therefore, the NMU system fulfils the criteria for controlling vascular reactivity in man.

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Mori et al. (2005). EMBO J 24: 325-335

Szekeres et al. (2000). J Biol Chem 275: 20247-20250