Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1

1 We have determined the distribution of receptors for human urotensin-II (U-II) in human and rat CNS and peripheral tissues. 2 In rat, [I-125]-U-II binding density was highest in the abducens nucleus of brainstem (139.6+/-14 amol mm(-2)). Moderate levels were detected in dorsal horn of spinal cord and lower levels in aorta (22.5+/-6 amol mm(-2)). 3 In human tissues density was highest in skeletal muscle and cerebral cortex (similar to 30 amol mm(-2)), with lower levels (<15 amol mm-2) in kidney cortex and left ventricle. Little binding was identified in atria, conducting system of the heart and lung parenchyma. 4 Receptor density was less in human coronary artery smooth muscle (14.6+/-3 amol mm(-2), n=10) than rat aorta with no significant difference between normal and atherosclerotic vessels. 5 In human skeletal muscle [I-125]-U-II bound to a single receptor population with K-D = 0.24+/-0.17 nM and B-max = 1.97+/-1.1 fmol mg(-1) protein (n=4). 6 U-II contracted human coronary, mammary and radial arteries, saphenous and umbilical veins with sub-nanomolar EC50 values. U-II was 50 times more potent in arteries and <10 times more potent in veins than endothelin-1 (ET-1). The maximum response to U-II (similar to 20% of control KCl) was significantly less than to ET-I (similar to 80% KCI). In contrast, in rat aorta, U-II and ET-1 were equipotent with similar maximum responses. 7 This is the first report of high affinity receptors for [I-125]-U-II in human CNS and peripheral tissues. This peptide produces potent, low efficacy, vasoconstriction in human arteries and veins. These data suggest a potential role for U-II in human physiology.