In vitro and in vivo pharmacological characterization of the novel UT receptor ligand [Pen5, DTrp7, Dab8] urotensin II(4-11) (UFP-803)
In vitro and in vivo pharmacological characterization of the novel UT receptor ligand [Pen5, DTrp7, Dab8] urotensin II(4-11) (UFP-803)
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DOI：
10.1038/sj.bjp.0706438
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发表时间：
2006-01-01
影响因子：
7.3
通讯作者：
Calò, G
中科院分区：
文献类型：
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作者：
Camarda, V;Spagnol, M;Calò, G
1 对新型尾加压素-II (U-II) 受体 (UT) 配体 [Pen(5)、DTrp(7)、Dab(8)]U-II(4-11) (UFP-803) 进行了药理学评估，并在体外和体内试验中与 urantide 进行了比较。2 在大鼠离体主动脉中，UFP-803 单独无活性，但浓度依赖性地将 U-II 的收缩反应替代为 U-II 的收缩反应。右图，揭示了竞争性拮抗作用，pA(2) 值为 7.46.3 在 HEK293(hUT) 和 HEK293(rUT) 细胞中室温下进行的 FLIPR [Ca2+](i) 测定中，U-II 增加了 [Ca2+](i)，pEC(50) 值为 8.11 和 8.48。 Urantide 和 UFP-803 作为激动剂没有活性，但通过以浓度依赖性方式降低激动剂最大效应来拮抗 U-II 的作用，表观 pK(B) 值在 8.45-9.05 范围内。在使用基于比色皿的 [Ca2+](i) 测定和 CHOhUT 细胞在 37°C 下进行的一系列单独实验中，urantide 模拟了 U-II 的 [Ca2+](i) 刺激作用，内在活性 (α) 为 0.80，而 UFP-803 显示出较小的 (α = 0.21) 但一致的残余激动剂活性。当在 22 摄氏度（与 FLIPR 实验相似的温度）下重复相同的实验时，urantide 显示出非常小的内在活性（α = 0.11），并且 UFP-803 作为激动剂完全失活。 4 在小鼠体内，UFP-803 (10 nmol kg(-1)) 拮抗 U-II (1 nmol kg(-1)) 诱导的各血管床血浆外渗增加，同时5 总之，UFP-803 是一种有效的 UT 受体配体，根据检测结果显示出竞争性/非竞争性拮抗剂行为。虽然 UFP-803 的效力不如 urantide，但它显示出较低的残留激动剂活性，因此可能是一种有用的药理学工具。
1 The novel urotensin-II (U-II) receptor (UT) ligand, [Pen(5), DTrp(7), Dab(8)]U-II(4-11) (UFP-803), was pharmacologically evaluated and compared with urantide in in vitro and in vivo assays.2 In the rat isolated aorta, UFP-803 was inactive alone but, concentration dependently, displaced the contractile response to U-II to the right, revealing a competitive type of antagonism and a pA(2) value of 7.46.3 In the FLIPR [Ca2+](i) assay, performed at room temperature in HEK293(hUT) and HEK293(rUT) cells, U-II increased [Ca2+](i) with pEC(50) values of 8.11 and 8.48. Urantide and UFP-803 were inactive as agonists, but antagonized the actions of U-II by reducing, in a concentration-dependent manner, the agonist maximal effects with apparent pK(B) values in the range of 8.45-9.05. In a separate series of experiments performed at 37 degrees C using a cuvette-based [Ca2+](i) assay and CHOhUT cells, urantide mimicked the [Ca2+](i) stimulatory effect of U-II with an intrinsic activity (alpha) of 0.80, while UFP-803 displayed a small (alpha = 0.21) but consistent residual agonist activity. When the same experiments were repeated at 22 degrees C (a temperature similar to that in FLIPR experiments), urantide displayed a very small intrinsic activity (alpha = 0.11) and UFP-803 was completely inactive as an agonist.4 In vivo in mice, UFP-803 (10 nmol kg(-1)) antagonized U-II (1 nmol kg(-1))-induced increase in plasma extravasation in various vascular beds, while being inactive alone.5 In conclusion, UFP-803 is a potent UT receptor ligand which displays competitive/ noncompetitive antagonist behavior depending on the assay. While UFP-803 is less potent than urantide, it displayed reduced residual agonist activity and as such may be a useful pharmacological tool.