Kosonen O, Kankaanranta H, Lähde M, Vuorinen P, Ylitalo P, Moilanen E
University of Tampere, Medical School, Department of Pharmacological Sciences, Finland.
J Pharmacol Exp Ther. 1998 Jul;286(1):215-20.
Two novel nitric oxide (NO)-releasing oxatriazole derivatives, GEA 3162 and GEA 3175, and an earlier known NO donor, S-nitroso-N-acetylpenicillamine (SNAP), inhibited cell proliferation and enhanced cGMP production in a concentration-dependent manner in human lymphocytes activated by lectin mitogen concanavalin A (ConA). The possible mediator role of cGMP in the antiproliferative action of NO donors was tested by pharmacological means. An inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one, inhibited NO donor-induced cGMP production, whereas the antiproliferative action of NO donors remained unaltered. Phosphodiesterase inhibitors zaprinast and 3-isobutyl-1-methylxanthine potentiated and prolonged NO donor-induced increase in the concentrations of cGMP but did not enhance the antiproliferative action of NO donors. In addition, two analogs of cGMP, 8-bromo-cGMP and a more cell-permeable compound, 8-p-chlorophenylthio-cGMP, did not inhibit ConA-stimulated lymphocyte proliferation when used in concentrations of up to 300 microM. At millimolar concentrations, 8-bromo-cGMP had a moderate inhibitory action. These results suggest that nitric oxide-releasing oxatriazole derivatives inhibit proliferative responses in human lymphocytes by a cGMP-independent manner.
两种新型释放一氧化氮（NO）的恶二唑衍生物GEA 3162和GEA 3175，以及一种较早已知的NO供体S-亚硝基-N-乙酰青霉胺（SNAP），在由凝集素促细胞分裂剂伴刀豆球蛋白A（ConA）激活的人淋巴细胞中，以浓度依赖性方式抑制细胞增殖并增强环磷酸鸟苷（cGMP）的产生。通过药理学方法测试了cGMP在NO供体抗增殖作用中的可能介导作用。鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮抑制NO供体诱导的cGMP产生，而NO供体的抗增殖作用保持不变。磷酸二酯酶抑制剂扎普司特和3-异丁基-1-甲基黄嘌呤增强并延长了NO供体诱导的cGMP浓度增加，但并未增强NO供体的抗增殖作用。此外，cGMP的两种类似物8-溴-cGMP和一种细胞通透性更强的化合物8-对氯苯硫基-cGMP，在浓度高达300微摩尔时，并未抑制ConA刺激的淋巴细胞增殖。在毫摩尔浓度下，8-溴-cGMP具有中等抑制作用。这些结果表明，释放一氧化氮的恶二唑衍生物通过非cGMP依赖的方式抑制人淋巴细胞的增殖反应。
