Iimura O, Kusano E, Amemiya M, Muto S, Ikeda U, Shimada K, Asano Y
Department of Nephrology, Jichi Medical School, Minamikawachi, Japan.
Eur J Pharmacol. 1996 Feb 5;296(3):319-26. doi: 10.1016/0014-2999(95)00712-1.
We examined whether dipyridamole affected interleukin-1beta-stimulated nitric oxide (NO) production by cultured rat vascular smooth muscle cells. Interleukin-1beta stimulated the production of nitrite and nitrate, stable metabolites of NO, in a dose- and time-dependent manner in vascular smooth muscle cells. Dipyridamole (1-100 mu M) enhanced interleukin-1beta-induced nitrite production in a dose- and time-dependent manner. The mRNA expression of inducible NO synthase was up-regulated by dipyridamole (0.3-10 mu M) treatment in a dose-dependent manner. Both 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) and dibutyryl adenosine 3',5'-cyclic monophosphate (db-cAMP) enhanced the nitrite production in the presence of interleukin-1beta. Dipyridamole up-regulated the effect of both 8-bromo-cGMP and db-cAMP on the interleukin-1beta-induced nitrite production. Dipyridamole increased the intracellular cAMP content in the presence of interleukin-1beta (10 ng/ml), but did not affect the intracellular cGMP content. 8R*,9S*,11S*-(-)-9-hydroxy-9-n-hexyloxy-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo-(a,g)-cy cloocta ++-(c,d,e)-trinden-1-one (KT 5720), a selective inhibitor of cAMP-dependent protein kinase, abolished the enhancement of interleukin-1beta-induced nitrite production by dipyridamole, whereas 8R*,9S*,11S*-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-ep oxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cyclo-octa-(c,d,e)-tr inden-1-one (KT 5823), an inhibitor of cGMP-dependent protein kinase, did not attenuate the enhancement. Furthermore, Rolipram and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20-1724), cAMP-specific phosphodiesterase type IV inhibitors, augmented the interleukin-1beta-induced nitrite production. We concluded that dipyridamole enhanced the interleukin-1beta-induced NO production via an increase in intracellular cAMP content in cultured rat vascular smooth muscle cells.
我们研究了双嘧达莫是否会影响培养的大鼠血管平滑肌细胞中白细胞介素 -1β刺激的一氧化氮（NO）生成。白细胞介素 -1β以剂量和时间依赖性方式刺激血管平滑肌细胞中NO的稳定代谢产物亚硝酸盐和硝酸盐的生成。双嘧达莫（1 - 100 μM）以剂量和时间依赖性方式增强白细胞介素 -1β诱导的亚硝酸盐生成。双嘧达莫（0.3 - 10 μM）处理以剂量依赖性方式上调诱导型一氧化氮合酶的mRNA表达。8 - 溴鸟苷3',5'-环磷酸（8 - 溴 - cGMP）和二丁酰腺苷3',5'-环磷酸（db - cAMP）在存在白细胞介素 -1β的情况下均增强亚硝酸盐生成。双嘧达莫上调8 - 溴 - cGMP和db - cAMP对白细胞介素 -1β诱导的亚硝酸盐生成的作用。双嘧达莫在存在白细胞介素 -1β（10 ng/ml）的情况下增加细胞内cAMP含量，但不影响细胞内cGMP含量。8R*,9S*,11S*-(-)-9 - 羟基 - 9 - 正己氧基 - 8 - 甲基 - 2,3,9,10 - 四氢 - 8,11 - 环氧 - 1H,8H,11H - 二级标题2,7b,11a - 三氮杂二苯并-(a,g)-环辛 ++-(c,d,e)-三亚苯 - 1 - 酮（KT 5720），一种cAMP依赖性蛋白激酶的选择性抑制剂，消除了双嘧达莫对白细胞介素 -1β诱导的亚硝酸盐生成的增强作用，而8R*,9S*,11S*-(-)-9 - 甲氧基甲酰基 - 8 - 甲基 - 2,3,9,10 - 四氢 - 8,11 - 环氧 - 1H,8H,11H - 2,7b,11a - 三氮杂二苯并-(a,g)-环辛 - (c,d,e)-三亚苯 - 1 - 酮（KT 5823），一种cGMP依赖性蛋白激酶的抑制剂，并未减弱这种增强作用。此外，咯利普兰和4 - (3 - 丁氧基 - 4 - 甲氧基苄基)-2 - 咪唑啉酮（Ro - 2图注0 - 1724），IV型cAMP特异性磷酸二酯酶抑制剂，增强白细胞介素 -1β诱导的亚硝酸盐生成。我们得出结论，双嘧达莫通过增加培养的大鼠血管平滑肌细胞内cAMP含量来增强白细胞介素 -1β诱导的NO生成。
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