选择性腺苷A2受体激动剂在缺氧反应中增强促红细胞生成素的产生。

T Ohigashi, J Nakashima, S Aggarwal, J Brookins, K Agrawal, J W Fisher
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摘要

本研究的目的是表征两种新的腺苷A2激动剂2-(对-(2-羧乙基)苯基氨基)-5'- n -乙基羧氨基腺苷(CGS-21680)和N6-(2(3,5-二甲氧基苯基)-2-(2-甲基苯基)乙基)-腺苷(DPMA)对体内和体外促红细胞生成素(EPO)产生的影响。静脉注射CGS-21680 (100 ~ 500 nmol/kg小鼠/天)和DPMA (50 ~ 500 nmol/kg小鼠/天)4天后,缺氧红细胞增多症小鼠血清EPO水平显著升高。CGS-21680 (10(-7) ~ 10(-6) mol/L)和DPMA (10(-8) ~ 10(-5) mol/L)在1% O2中培养18小时后,也能显著提高克隆的EPO产生肝癌Hep3B细胞的EPO水平。两种化合物在孵育1小时后也以剂量依赖的方式显著增加细胞cAMP水平。用氚化CGS-21680进行A2受体结合实验,发现Hep3B细胞膜上存在一种单一类型的腺苷受体结合位点,解离常数为132.9 nmol/L,结合能力为270.6 fmol/mg蛋白。CGS-21680与氚化CGS-21680的Ki竞争结合值分别为217 nmol/L和86.8 nmol/L。这些结果表明,体内和体外缺氧时,腺苷A2受体的激活会增加EPO的产生。
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Enhancement of erythropoietin production by selective adenosine A2 receptor agonists in response to hypoxia.

The purpose of this study was to characterize the effects of two new adenosine A2 agonists, 2-(p-(2-carboxyethyl)phenethyl amino)-5'-N-ethylcarboxamidoadenosine (CGS-21680) and N6-(2(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine (DPMA), on erythropoietin (EPO) production in vivo and in vitro. Intravenous injections of CGS-21680 (100 to 500 nmol/kg mouse/day) and DPMA (50 to 500 nmol/kg mouse/day) for 4 days produced significant increases in serum levels of EPO in exhypoxic polycythemic mice. CGS-21680 (10(-7) to 10(-6) mol/L) and DPMA (10(-8) to 10(-5) mol/L) also produced significant increases in medium levels of EPO in a cloned EPO-producing Hep3B hepatocellular carcinoma cell line after 18 hours of incubation in 1% O2. Both compounds also increased cellular cAMP levels significantly in a dose-dependent manner after 1 hour of incubation. A2 receptor binding assays with tritiated CGS-21680 revealed a single type of adenosine receptor binding site on Hep3B cell membranes with a dissociation constant of 132.9 nmol/L and a binding capacity of 270.6 fmol/mg protein. The Ki competition binding values versus tritiated CGS-21680 were 217 nmol/L for CGS-21680 and 86.8 nmol/L for DPMA. These results indicate that adenosine A2 receptor activation amplifies EPO production in response to hypoxia, both in vivo and in vitro.

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