1 Urotensin-II (U-II) and its G-protein-coupled receptor, GPR14, are expressed within mammalian cardiac and peripheral vascular tissue and, as such, may regulate mammalian cardiovascular function. The present study details the vasoconstrictor pro®le of this cyclic undecapeptide in di erent vascular tissues isolated from a diverse range of mammalian species (rats, mice, dogs, pigs, marmosets and cynomolgus monkeys). 2 The vasoconstrictor activity of human U-II was dependent upon the anatomical origin of the vessel studied and the species from which it was isolated. In the rat, constrictor responses were most pronounced in thoracic aortae and carotid arteries: 7log[EC 50 ]s 9.09+0.19 and 8.84+0.21, R max s 143+21 and 67+26% 60 mM KCl, respectively (compared, for example, to 7log[EC 50 ] 7.90+0.11 and R max 142+12% 60 mM KCl for endothelin-1 [ET-1] in thoracic aortae). Responses were, however, absent in mice aortae (7log [EC 50 ] 56.50). These ®ndings were further contrasted by the observation that U-II was a`coronary-selective' spasmogen in the dog (7log [EC 50 ] 9.46+0.11, R max 109+23% 60 mM KCl in LCX coronary artery), yet exhibited a broad spectrum of vasoconstrictor activity in arterial tissue from Old World monkeys (7log [EC 50 ]s range from 8.96+0.15 to 9.92+0.13, R max s from 43+16 to 527+135% 60 mM KCl). Interestingly, signi®cant di erences in reproducibility and vasoconstrictor e cacy were seen in tissue from pigs and New World primates (vessels which responded to noradrenaline, phenylephrine, KCl or ET-1 consistently). 3 Thus, human U-II is a potent, e cacious vasoconstrictor of a variety of mammalian vascular tissues. Although signi®cant species/anatomical variations exist, the data support the hypothesis that U-II in¯uences the physiological regulation of mammalian cardiovascular function. British Journal of Pharmacology (2000) 131, 1262 ± 1274 Keywords: Urotensin-II; GPR14; SENR; endothelin-1; somatostatin; vascular reactivity; spasmogen; coronary artery; endothelium; vasoconstriction Abbreviations: FLIPR,¯uorescent imaging plate reader; GPCR, guanosine triphosphate-binding protein [G-protein]-coupled receptor; LAD coronary artery, left anterior descending coronary artery; LCX, left circum¯ex coronary artery; SENR, sensory epithelial neuropeptide-like receptor; U-II, Urotensin-II
IntroductionThe integrated control of cardiovascular homeostasis is achieved through a combination of direct neuronal control and systemic activation of the neurohumoral axis. The principal mammalian vasoactive factors of this axis (angiotensin-II, endothelin [ET]-1, noradrenaline) exert their haemodynamic e ects exclusively via interactions with speci®c seven transmembrane heterotrimeric G-protein-coupled receptors (GPCRs). Drugs which antagonize such interactions constitute one of the most successful classes of therapeutic agents identi®ed to date (Stadel et al., 1997; Wilson et al., 1998). Nowhere is this more evident than within the vasculature where numerous agents have been developed successfully for the clinical ...