Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14

Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide whic h was originally isolated from fish spinal cords(1,2), and which has recent ly been cloned from man(3). Here we describe the identification of an orpha n human G-protein-coupled receptor homologous to rat GPR14 (refs 4, 5) and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high af finity, and the binding is functionally coupled to calcium mobilization. Hu man U-II is found within both vascular and cardiac tissue (including corona ry atheroma) and effectively constricts isolated arteries from non-human pr imates. The potency of vasoconstriction of U-II is an order of magnitude gr eater than that of endothelin-1, making human U-II the most potent mammalia n vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a respons e associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endo crine tissues, it may have additional activities.