Urotensins are neuropeptide secreted from the urophysis in the caudal neurosecretory system of the fishes. Two bioactive Urotensins, U1 and UII have been cloned from various species including mammals. UI is 41 aa peptide, which showed prolonged hypotensive effects in mammals. It is structurally similar to mammalian corticotropin-releasing factor. UII is a vasoactive 'somatostatin-like" 12-aa cyclic peptide with similarity to somatostatin-14. Human UII is composed of only 11 aa residues, while fish and frog UII possess 12 and 13 aa, respectively. The cyclic region of the UII, which is responsible for the biological activity of the peptide, has been fully conserved from fish to human. UII expression has been observed predominantly in the spinal cord. Recently, an orphan human G-protein coupled receptor homologous to rat GPR14 has been identified as the receptor for UII (2). GPR14 is expressed predominantly in cardiovascular tissue. Human UII effectively stimulated total peripheral resistance in anesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. GPR14 (rat 386 aa and human 389 aa, ~75% homology) contains 7 transmembrane domains. It is most closely related to somatostatin receptor4. GPR14 is mostly expressed in the heart and pancreas, while low expression was detected in the brain.