Human urotensin-II is a potent vasoactive peptide: Pharmacological characterization in the rat, mouse, dog and primate

The observation that the novel G-protein-coupled receptor (GPCR) GPR14 and its cognate ligand, urotensin-II (U-II), are expressed within the mammalian vasculature raises the possibility that they may influence cardiohemodynam ic humeostasis. To this end, this study examined the vasoactive properties of U-II in rodents, dogs and primates. In vitro, human U-II was a sustained vasoconstrictor with a potency (pD(2)s less than or equal to 9) approximat ely an order of magnitude greater than that seen with endothelin-1 (ET-1), making it one of the roost, if not the most, potent mammalian vasoconstrict or identified to date. However, in vitro responses exhibited significant an atomical and/or species-dependency, that is, human U-II was a selective 'ao rto-coronary' vasoconstrictor in rats and dogs, inactive in mice and contra cted all primate arteries studied. In vivo, this peptide evoked a complex, dose-dependent hemodynamic response in the anesthetized primate, culminatin g in severe myocardial depression and fatal circulatory collapse. As such, U-II may represent a novel neurohumoral regulator of mammalian cardiovascul ar physiology and pathology in particular disorders characterized by aberra nt vascular smooth muscle and/or myocardial function.