Urantide: An ultrapotent urotensin II antagonist peptide in the rat aorta

Abstract

In this study we describe the ability of two human urotensin-II (hU-II) derivatives [Pen 5,Orn 8]hU-II(4-11) and [Pen 5,DTrp 7,Orn 8]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 pK B = 7.4 ± 0.06 (n = 12) and pK B = 8.3 ± 0.09 (n = 12), respectively. In contrast, neither [Pen 5,Orn 8]-hU-II(4-11) nor urantide (1 μM each) was able to modify noradrenaline- or endothelin 1-induced contractile effects. At micromolar concentrations, [Pen 5,Orn 8]hU-II(4-11) produced weak (≤25% of hU-II maximum) agonist responses in the rat aorta, whereas urantide was totally uneffective as agonist up to 1 μM. In addition, [Pen 5,Orn 8]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 (pK i = 7.7 ± 0.05, n = 4 and pK i = 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.