Cheng M K, Doumad A B, Jiang H, Falck J R, McGiff J C, Carroll M A
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, U.S.A.
Br J Pharmacol. 2004 Feb;141(3):441-8. doi: 10.1038/sj.bjp.0705640. Epub 2004 Jan 12.
Activation of rat adenosine2A receptors (A2A R) dilates preglomerular microvessels (PGMV), an effect mediated by epoxyeicosatrienoic acids (EETs). Incubation of PGMV with a selective A2A R agonist, 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 100 microM), increased isolated PGMV EET levels to 7.57+/-1.53 ng mg-1 protein from 1.06+/-0.22 ng mg-1 protein in controls (P<0.05), without affecting hydroxyeicosatetraenoic acid (HETE) levels (10.8+/-0.69 vs 11.02+/-0.74 ng mg-1 protein). CGS 21680-stimulated EETs was abolished by preincubation with an A2A R antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) (100 microM). A selective epoxygenase inhibitor, methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH; 12 microM) prevented CGS 21680-induced increase in EETs, indicating inhibition of de novo synthesis of EETs. In pressurized (80 mmHg) renal arcuate arteries (110-130 microm) preconstricted with phenylephrine (20 nM), superfusion with CGS 21680 (0.01-10 microM) increased the internal diameter (i.d.) concentration-dependently; vasodilation was independent of nitric oxide and cyclooxygenase activity. CGS 21680 (10 microM) increased i.d. by 32+/-6 microm; vasodilation was prevented by inhibition of EET synthesis with MS-PPOH. Addition of 3 nM 5,6-EET, 8,9-EET and 11,12-EET increased i.d. by 53+/-9, 17+/-4 and 53+/-5 microm, respectively, whereas 14,15-EET was inactive. The responses to 5,6-EET were, however, significantly inhibited by indomethacin. We conclude that 11,12-EET is the likely mediator of A2A R-induced dilation of rat PGMV. Activation of A2A R coupled to de novo EET stimulation may represent an important mechanism in regulating preglomerular microvascular tone. British Journal of Pharmacology (2004) 141, 441-448. doi:10.1038/sj.bjp.0705640
大鼠腺苷2A受体（A2A R）的激活可使肾小体前微动脉（PGMV）扩张，这一效应由环氧二十碳三烯酸（EETs）介导。将PGMV与选择性A2A R激动剂2 - p -（2 - 羧乙基）苯乙氨基 - 5'- N - 乙基羧酰胺腺苷（CGS 21680；100微摩尔）一起孵育，可使分离的PGMV中EET水平从对照中的1.06±0.22纳克/毫克蛋白质增加至7.57±1.53纳克/毫克蛋白质（P<0.05），而不影响羟基二十碳四烯酸（HETE）水平（10.8±0.69对11.02±0.74纳克/毫克蛋白质）。用A2A R拮抗剂4 -（2 - [7 - 氨基 - 2 -（2 - 呋喃基）[1,2,4]三唑并[2,3 - a][1,3,5]三嗪 - 5 - 基氨基]乙基）苯酚（ZM241385）（100微摩尔）预孵育可消除CGS 21680刺激的EETs。选择性环氧合酶抑制剂甲基磺酰 - 炔丙氧基苯基己酰胺（MS - PPOH；12微摩尔）可阻止CGS 21680诱导的EETs增加，表明抑制了EETs的从头合成。在由去氧肾上腺素（20纳摩尔）预收缩的加压（80毫米汞柱）肾弓状动脉（110 - 130微米）中，用CGS 21680（0.01 - 10微摩尔）进行灌流可使内径（i.d.）呈浓度依赖性增加；血管舒张与一氧化氮和环氧化酶活性无关。CGS 21680（10微摩尔）使内径增加32±6微米；用MS - PPOH抑制EET合成可阻止血管舒张。添加3纳摩尔的5,6 - EET、8,9 - EET和11,12 - EET分别使内径增加53±9、17±4和53±5微米，而14,15 - EET无活性。然而吲哚美辛可显著抑制对5,6 - EET的反应。我们得出结论，11,12 - EET可能是A2A R诱导大鼠PGMV扩张的介质。与EET从头刺激偶联的A2A R激活可能是调节肾小体前微血管张力的重要机制。《英国药理学杂志》（2004年）141卷，441 - 448页。doi:10.1038/sj.bjp.0705640
