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. British Journal of Pharmacology (2002) 137 , 579–588. doi: 10.1038/sj.bjp.0704924