Rossowski Wojciech J, Cheng Beng-L, Taylor John E, Datta Rakesh, Coy David H
Peptide Research Laboratories, Department of Medicine, Tulane University Medical Science Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Eur J Pharmacol. 2002 Mar 8;438(3):159-70. doi: 10.1016/s0014-2999(02)01341-9.
Human urotensin II-(1-11) and its N-terminally shortened analogues, human urotensin II-(4-11)-OH and human urotensin II-(4-11)-NH2 are potent vasoconstrictor peptides in isolated rat thoracic aorta. Human urotensin II-induced tonic aorta ring contractions are inhibited by the Ca2+ channel antagonists, verapamil, nitrendipine and diltiazem; D609 (Tricyclodecan-9-yl-xanthogenate, K), selective inhibitor of phosphatidylcholine-specific phospholipase C and partially by phospholipase C inhibitor U-73122 [1-[6-((17ss-3 Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-25-dione] and a selective inhibitor of phosphatidyl-inositol-specific phospholipase C-ET-18-OCH3 (Edelfosine,1-O-octadecyl-2O-methyl-rac-glycero-3-phosphorylcholine); protein kinase C inhibitors, chelerythrine and NPC-15437 [S-2,6-diamino-N-[[1-(1-oxotridecyl)-2-piperidinyl]methyl]-hexanamide dihydrochloride]; tyrosine kinase inhibitors, genistein and tyrphostin B42 and Rho-kinase inhibitor HA-1077 [1-(5-isoquinolinylsulfonyl)-homopiperazine dihydrochloride]. This indicates that human urotensin II-induced tonic contractions of the rat aorta are mediated by phospholipase C, protein kinase C, tyrosine kinases and Rho-kinase related pathways. In the high K+ medium, human urotensin II induces dose-dependent phasic oscillations of aortic rings. These are inhibited by Ca2+ channel antagonists, the phospholipase C inhibitor, U-73122 and protein kinase C inhibitors, chelerythrine and NPC-15437, indicating that human urotensin II-induced phasic oscillations of the rat aorta are mediated by phospholipase C and protein kinase C-dependent pathways. Given their close structural similarity, several somatostatin analogues, importantly containing DCys5 and DTrp7 and expressing different degrees of somatostatin receptor antagonist activity, were tested for possible inhibitory effects on human urotensin II-induced contractions of the rat aorta rings. Pre-incubation of rat aorta rings in the presence of somatostatin analogues, which are preferentially sst2 specific binders: PRL-2882; PRL-2903 and PRL-2915 at micro-molar concentrations significantly blocked the development of human urotensin II-induced tonic contractions. Somatostatin receptor antagonists dose-dependently inhibited human urotensin II-induced Ca2+ transients in rat thoracic aorta rings. These somatostatin receptor antagonists displayed moderate affinities for recombinant rat and human urotensin II receptor binding sites. The data support the suggestion that urotensin II receptor and somatostatin type 2/5 receptors display similar surface topologies and that analogues of somatostatin could provide useful lead compounds for the development of more potent urotensin II receptor antagonists.
人尿紧张素II -（1 - 11）及其N端截短类似物，人尿紧张素II -（4 - 11）- OH和人尿紧张素II -（4 - 11）- NH2是离体大鼠胸主动脉中有效的血管收缩肽。人尿紧张素II诱导的主动脉环强直性收缩受到钙通道拮抗剂维拉帕米、尼群地平和地尔硫卓的抑制；D609（三环癸烷-9-基-黄原酸酯，K），磷脂酰胆碱特异性磷脂酶C的选择性抑制剂，以及部分受到磷脂酶C抑制剂U - 73122 [1 - [6 - （（17β - 3 - 甲氧基雌甾-1,3,5（10）-三烯-17 - 基）氨基）己基]-1H - 吡咯-2,5 - 二酮]和磷脂酰肌醇特异性磷脂酶C - ET - 18 - OCH3（依地福新，1 - O - 十八烷基-2 - O - 甲基-rac - 甘油-3 - 磷酸胆碱）的选择性抑制剂的抑制；蛋白激酶C抑制剂白屈菜红碱和NPC - 15437 [S - 2,6 - 二氨基-N - [[1 - （1 - 氧代十三烷基）-2 - 哌啶基]甲基]-己酰胺二盐酸盐]；酪氨酸激酶抑制剂染料木黄酮和 tyrphostin B42以及Rho激酶抑制剂HA - 1077 [1 - （5 - 异喹啉磺酰基）-高哌嗪二盐酸盐]。这表明人尿紧张素II诱导的大鼠主动脉强直性收缩是由磷脂酶C、蛋白激酶C、酪氨酸激酶和Rho激酶相关途径介导的。在高钾培养基中，人尿紧张素II诱导主动脉环的剂量依赖性相位振荡。这些振荡受到钙通道拮抗剂、磷脂酶C抑制剂U - 73122以及蛋白激酶C抑制剂白屈菜红碱和NPC - 15437的抑制，表明人尿紧张素II诱导的大鼠主动脉相位振荡是由磷脂酶C和蛋白激酶C依赖性途径介导的。鉴于它们结构上的相似性，测试了几种生长抑素类似物，重要的是含有DCys5和DTrp7并表现出不同程度生长抑素受体拮抗剂活性，以探究其对人尿紧张素II诱导的大鼠主动脉环收缩的可能抑制作用。在微摩尔浓度下，优先作为sst2特异性结合剂的生长抑素类似物PRL - 2882、PRL - 2903和PRL - 2915预孵育大鼠主动脉环，可显著阻断人尿紧张素II诱导的强直性收缩的发展。生长抑素受体拮抗剂剂量依赖性地抑制人尿紧张素II诱导的大鼠胸主动脉环中的钙瞬变。这些生长抑素受体拮抗剂对重组大鼠和人尿紧张素II受体结合位点表现出中等亲和力。数据支持以下观点：尿紧张素II受体与生长抑素2/5型受体具有相似的表面拓扑结构，并且生长抑素类似物可为开发更有效的尿紧张素II受体拮抗剂提供有用的先导化合物。
