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

Abstract

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, [125I]-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 (-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 [125I]-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 (-20% of control KCl) was significantly less than to ET-1 (-80% KCl). 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 [125I]-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.