Urantide: an ultrapotent urotensin II antagonist peptide in the rat aorta.
In this study we describe the ability of two human urotensin-II (hU-II) derivatives [Pen5,Orn8]hU-II(4-11) and [Pen5,DTrp7,Orn8]hU-II(4-11) (urantide) to block hU-II-induced contractions in the rat isolated thoracic aorta. Both compounds competitively antagonized hU-II- induced effects with pKB=7.4+/-0.06 (n=12) and pKB=8.3+/-0.09 (n=12), respectively. In contrast, neither [Pen5,Orn8]hU-II(4-11) nor urantide (1 microm each) was able to modify noradrenaline- or endothelin 1-induced contractile effects. At micromolar concentrations, [Pen5,Orn8]hU-II(4-11) produced weak (< or =25% of hU-II maximum) agonist responses in the rat aorta, whereas urantide was totally uneffective as agonist up to 1 microm. In addition, [Pen5,Orn8]hU-II(4-11) and urantide displaced [125I]urotensin II from specific binding at hU-II recombinant receptors (UT receptors) transfected into CHO/K1 cells (pKi=7.7+/-0.05, n=4 and pKi=8.3+/-0.04, n=4, respectively). To our knowledge, urantide is the most potent UT receptor antagonist so far described, and might represent a useful tool for exploring the (patho)physiological role of hU-II in the mammalian cardiovascular system.
Patacchini
Riccardo
R
Department of Pharmacology, Menarini Ricerche SpA, Via Rismondo 12/A, Florence 50131, Italy. chimfarm@menarini-ricerche.it
Santicioli
Paolo
P
Giuliani
Sandro
S
Grieco
Paolo
P
Novellino
Ettore
E
Rovero
Paolo
P
Maggi
Carlo Alberto
CA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014579:Urotensins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019332:Endothelin-1; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D014579:Urotensins; D014662:Vasoconstrictor Agents; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C029677:urotensin II; D009638:Norepinephrine