Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey

1 Urotensin-II (U-II) and its G-protein-coupled receptor, GPR14, are expres sed within mammalian cardiac and peripheral vascular tissue and, as such, m ay regulate mammalian cardiovascular function. The present study details th e vasoconstrictor profile of this cyclic undecapeptide in different vascula r tissues isolated from a diverse range of mammalian species (rats, mice, d ogs, pigs, marmosets and cynomolgus monkeys). 2 The vasoconstrictor activity of human U-II was dependent upon the anatomi cal 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: -log[EC50]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 - log[EC50] 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 (-log[ EC50] <6.50). These findings were further contrasted by the observation tha t U-II was a 'coronary-selective' spasmogen in the dog (- log[EC50] 9.46+/- 0.11, R-max 109+/-23% 60 mM KCl in LCX coronary artery), yet exhibited a br oad spectrum of vasoconstrictor activity in arterial tissue from Old World monkeys (-log[EC50]s range from 8.96+/-0.15 to 9.92+/-0.13, R(max)s from 43 +/- 16 to 527 +/- 135% 60 mM KCI). Interestingly, significant differences in reproducibility and vasoconstrictor efficacy were seen in tissue from pi gs and New World primates (vessels which responded to noradrenaline, phenyl ephrine, KCl or ET-1 consistently). 3 Thus, human U-II is a potent, efficacious vasoconstrictor of a variety of mammalian vascular tissues. Although significant species/anatomical variat ions exist, the data support the hypothesis that U-II influences the physio logical regulation of mammalian cardiovascular function.