Human neuromedin U-25, a ligand for the G-protein coupled orphan FM-3 receptor, constrictcs human arteries in vitro Janet J. Maguire & Anthony P. Davenport. Clinical Pharmacology Unit, University of Cambridge, Level 6 Centre for Clinical Investigation, Box 110 Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.

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The human orphan FM-3 receptor (Tan et al., 1998) has recently been paired with its cognate ligand, neuromedin U (NMU) (Fujii et al., 2000; Szekeres et al., 2000). In conscious rats in vivo, NMU-25 selectivity attenuated superior mesenteric blood flow (Gardiner et al., 1990). The effect of NMU-25 on the human vasculature has not been reported. Our aim was to compare the potential of human NMU-25 (hNMU-25) as a constrictor of human arteries, in vitro, to the potent constrictor, endothelin-1 (ET-1).

Human coronary (CA) and radial (RA) arteries were obtained, with ethical approval, from patients undergoing heart transplantation (n=9) or receiving CA bypass grafts (n=7). Arterial rings (4mm) were set up in 5ml organ baths containing oxygenated Krebs' solution (37°C) for isometric force recordings. Cumulative concentration-response curves were constructed to hNMU-25 and ET-1 (1x10^-10-310^-7M) and the experiments terminated by addition of 100mM KCl to determine the maximum contractile response for each tissue. Agonist responses were expressed as a percentage of the KCl response. Data were fitted to a four parameter logistic equation (Fig P, Biosoft, Cambridge UK). Data are the mean ± s.e.mean, n-values are the number of patients from whom arteries were obtained and data were compared using Student's two-tailed t-test, with significance set at P<0.05.

Fig. 1. Constrictor activity of ET-1 and hNMU-25.

Human NMU-25 contracted CA with pD₂ = 8.62±0.13 (n=7) and RA with pD₂ = 8.79±0.49 (n=4). These values were not significantly different from pD₂ values obtained for ET-1 (CA pD₂ = 8.14±0.20, n=8; RA pD₂ = 8.10±0.13, n=5) NMU-25 failed to contract CA from two patients and RA from two patients whereas ET-1 contracted all arteries tested. The maximum response to hNMU-25 was significantly less than that for ET-1 in both CA (33±12 %KCl compared to 78±9 %KCl respectively, P<0.01) and in RA (18±2 %KCl compared to 54±7 %KCl respectively, P<0.005).

In conclusion, hNMU-25 possesses vasoconstrictor activity in human large arteries in vitro. The presence of this peptide in human plasma has not yet been detected therefore, the physiological or potential pathophysiological significance of this action remains to be clarified.

Supported by grants from the British Heart Foundation.

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