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Received for publication March 15, 2004.
Revised May 6, 2004.
Accepted for publication May 12, 2004.
ABSTRACT Urotensin-II (U II) is a cyclic peptide now described as the most potent vasoconstrictor known. U II binds to a specific G-protein coupled receptor, formerly the orphan receptor GPR14, now renamed urotensin receptor (UT receptor), and present in mammalian species. ACT 058362 (1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt) is a new potent and specific antagonist of the human UT receptor. ACT 058362 antagonizes the specific binding of 125I-Iabeled U II on natural and recombinant cells carrying the human UT receptor with a high affinity in the low nanomolar range and a competitive mode of antagonism, revealed only with prolonged incubation times. ACT 058362 also inhibits U II induced calcium mobilization and mitogen-activated protein kinase (MAPK) phosphorylation. The binding inhibitory potency of ACT 058362 is more than 100-fold less on the rat than on the human UT receptor, which is reflected in a pD'2 of 5.2 for inhibiting contraction of isolated rat aortic rings induced by U II. In functional assays of short incubation times, ACT 058362 behaves as an apparent non-competitive inhibitor. In vivo, intravenous ACT 058362 prevents the no-reflow phenomenon, which follows renal artery clamping in rats, without decreasing blood pressure, and prevents the subsequent development of acute renal failure and the histological consequences of ischemia. In conclusion, the in vivo efficacy of the specific UT receptor antagonist ACT 058362 reveals a role of endogenous U II in renal ischemia. As a selective renal vasodilator, ACT 058362 may be effective in other renal diseases.
Key words:
ACT-058362, UT receptors, renal failure, renal ischemia, urotensin, urotensin receptor antagonist
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