Patacchini Riccardo, Santicioli Paolo, Giuliani Sandro, Grieco Paolo, Novellino Ettore, Rovero Paolo, Maggi Carlo Alberto
Department of Pharmacology, Menarini Ricerche SpA, Via Rismondo 12/A, Florence 50131, Italy.
Br J Pharmacol. 2003 Dec;140(7):1155-8. doi: 10.1038/sj.bjp.0705555.
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.
在本研究中，我们描述了两种人尾加压素II（hU-II）衍生物[Pen5,Orn8]hU-II(4 - 11)和[Pen5,DTrp7,Orn8]hU-II(4 - 11)（尿活性肽）在大鼠离体胸主动脉中阻断hU-II诱导的收缩的能力。两种化合物均竞争性拮抗hU-II诱导的效应，其pKB分别为7.4±0.06（n = 12）和8.3±0.09（n = 12）。相比之下，[Pen5,Orn8]hU-II(4 - 11)和尿活性肽（各1微摩尔）均不能改变去甲肾上腺素或内皮素1诱导的收缩效应。在微摩尔浓度下，[Pen5,Orn8]hU-II(4 - 11)在大鼠主动脉中产生微弱（≤hU-II最大效应的25%）的激动剂反应，而尿活性肽在高达1微摩尔时作为激动剂完全无作用。此外，[Pen5,Orn8]hU-II(4 - 11)和尿活性肽从转染到CHO/K1细胞中的hU-II重组受体（UT受体）的特异性结合位点上取代了[125I]尾加压素II（pKi分别为7.7±0.05，n = 4和8.3±0.04，n = 4）。据我们所知，尿活性肽是迄今为止所描述的最有效的UT受体拮抗剂，可能是探索hU-II在哺乳动物心血管系统中的（病理）生理作用的有用工具。
