Epoxyeicosatrienoic acids mediate adenosine-induced vasodilation in rat preglomerular microvessels (PGMV) via A2A receptors.
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
Cheng
M K
MK
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, U.S.A.
Doumad
A B
AB
Jiang
H
H
Falck
J R
JR
McGiff
J C
JC
Carroll
M A
MA
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
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