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 [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 p K B =7.4±0.06 ( n =12) and p K B =8.3±0.09 ( n =12), respectively. In contrast, neither [Pen 5 ,Orn 8 ]hU‐II(4–11) nor urantide (1 μ M 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 μ M . In addition, [Pen 5 ,Orn 8 ]hU‐II(4–11) and urantide displaced [ 125 I]urotensin II from specific binding at hU‐II recombinant receptors (UT receptors) transfected into CHO/K1 cells (p K i =7.7±0.05, n =4 and p K 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. British Journal of Pharmacology (2003) 140 , 1155–1158. doi: 10.1038/sj.bjp.0705555