Is urotensin-II the new endothelin?
Urotensin-II (U-II), a peptide isolated from the urophysis of teleost fish 35 years ago, is the endogenous ligand of the mammalian orphan receptor GPR14/SENR. Recently, human homologues of both the receptor (UT-II) and the peptide (hU-II) have been discovered. Following de-orphanization, hU-II was declared the 'new endothelin' as initial studies suggested similarities between the peptides, and in isolated arteries of cynomolgus monkey U-II was a more potent constrictor than endothelin-1 (ET-1), with equal efficacy. However, effects of U-II in vascular tissue from other mammalian species are variable and although potent, U-II exhibits a lesser maximal response than ET-1. In contrast, in humans U-II has emerged as a ubiquitious constrictor of both arteries and veins in vitro and elicits a reduction in blood flow in the forearm and skin microcirculation in vivo. In addition to direct vasoconstrictor activity on smooth muscle receptors, endothelium-dependent U-II-mediated vasodilatation has also been observed. Non-vascular, peripheral actions of U-II include potent inotropy and airway smooth muscle constriction and U-II and its receptor are present throughout rat brain implying a possible neurotransmitter or neuromodulatory role in the central nervous system. U-II is proposed to contribute to human diseases including atherosclerosis, cardiac hypertrophy, pulmonary hypertension and tumour growth. The development of selective receptor antagonists should help to clarify the relative importance of hU-II as a multifunctional peptide in mammalian systems and its role in disease. What is clear is that U-II is emerging as a new and potentially important mammalian transmitter.
Maguire
Janet J
JJ
Clinical Pharmacology Unit, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. jjm1003@medschl.cam.ac.uk
Davenport
Anthony P
AP
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D017386:Sequence Homology, Amino Acid; D014579:Urotensins / Q000494:pharmacology / Q000502:physiology*
D016232:Endothelins; D014579:Urotensins; C029677:urotensin II