title: Epoxyeicosatrienoic acids mediate adenosine-induced vasodilation in rat preglomerular microvessels (PGMV) via A2A receptors.
abstract: 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
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, U.S.A.
authors.forename: M K
authors.initials: MK
authors.lastname: Cheng
authors.forename: A B
authors.initials: AB
authors.lastname: Doumad
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.forename: J R
authors.initials: JR
authors.lastname: Falck
authors.forename: J C
authors.initials: JC
authors.lastname: McGiff
authors.forename: M A
authors.initials: MA
authors.lastname: Carroll
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D010105:Oxygenases / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D001095:Arachidonic Acids; D004852:Epoxy Compounds; D043705:Receptor, Adenosine A2A; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid; D000241:Adenosine