act-058362 and Renal-Insufficiency

Urotensin II (U-II) is currently the most potent vasoconstrictor identified. This action is brought about via activation of a G(q/11)-protein coupled receptor (UT receptor). U-II activation of the UT receptor increases inositol phosphate turnover and intracellular Ca(2+). In addition to producing vasoconstriction, dilation and ionotropic effects have also been described. There is considerable variation in the responsiveness of particular vascular beds from the same and different species, including humans. Receptors for U-II are located peripherally on vascular smooth muscle (contractile responses) and endothelial cells (dilatory responses via nitric oxide). In humans, plasma U-II is elevated in heart failure, renal failure, liver disease, and diabetes. Iontophoresis of U-II in healthy volunteers produces vasodilation (of the forearm) while in patients with heart failure or hypertension a constriction is observed. To date there is only one clinical study using a UT receptor antagonist (palosuran) in diabetic patients with macroalbuminuria. This antagonist reduced albumin excretion, probably by increasing renal blood flow. Studies in other disease conditions are eagerly awaited. In summary, the U-II / UT receptor system has clinical potential, and for the anesthesiologist, this novel peptide-receptor system may be of use in the intensive care unit.

Topics: Animals; Calcium; Cricetinae; Cricetulus; Diabetes Mellitus; Heart Failure; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Polymerase Chain Reaction; Quinolines; Rats; Receptors, G-Protein-Coupled; Renal Insufficiency; Signal Transduction; Urea; Urotensins; Vasoconstriction

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. Palosuran (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 (125)I-labeled 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 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) value 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 noncompetitive 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.

Topics: Animals; Aorta, Thoracic; Disease Models, Animal; Humans; Ischemia; Kidney Diseases; Male; Quinolines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Renal Insufficiency; Urea; Urotensins; Vasoconstriction