Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ.

The interaction between adenosine and soluble epoxide hydrolase (sEH) in vascular response is not known. Therefore, we hypothesized that lack of sEH in mice enhances adenosine-induced relaxation through A2A adenosine receptors (AR) via CYP-epoxygenases and peroxisome proliferator-activated receptor γ (PPARγ). sEH-/- showed an increase in A2A AR, CYP2J, and PPARγ by 31%, 65%, and 36%, respectively, and a decrease in A1AR and PPARγ (30% and 27%, respectively) vs. sEH-/-. 5=-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A2A AR-agonist), and GW 7647 (PPARγ-agonist)-induced responses were tested with nitro-L-arginine methyl ester (L-NAME) (NO-inhibitor; 10-4 M), ZM-241385, SCH- 58261 (A2A AR-antagonists; 10-6 M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10-5 M), 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; 10 μM) or trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB, sEH-inhibitors; 10-5 M), and T0070907 (PPARγ-antagonist; 10-7 M). In sEH-/- mice, ACh response was not different from sEH-/- (P < 0.05), and L-NAME blocked ACh-responses in both sEH-/- and sEH-/- mice (P < 0.05). NECA (10-6 M)-induced relaxation was higher in sEH-/- (-12.94 × 3.2%) vs. sEH-/- mice (-5.35 × 5.2%); however, it was blocked by ZM-241385 (-22.42 × 1.9%) and SCH-58261(-30.04 × 4.2%). CGS-21680 (10-6 M)- induced relaxation was higher in sEH-/- (-37.4 × 5.4%) vs. sEH-/- (-2.14 × 2.8%). L-NAME (sEH-/-, -30.28 × 4.8%, P < 0.05) did not block CGS-21680-induced response, whereas 14,15- EEZE (-7.1 × 3.7%, P < 0.05) did. Also, AUDA and t-AUCB did not change CGS-21680-induced response in sEH-/- (P > 0.05), but reversed in sEH-/- (from -2.14 × 2.8% to -45.33 × 4.1%, and -63.37 × 7.2, respectively). PPARγ-agonist did not relax as CGS 21680 (-2.48 × 1.1 vs. -37.4 × 5.4%) in sEH-/-, and PPARγ- antagonist blocked (from -37.4 × 5.4% to -9.40 × 3.1) CGS 21680-induced relaxation in sEH-/-. Our data suggest that adenosine- induced relaxation in sEH-/- may depend on the upregulation of A2A AR, CYP2J, and PPARγ, and the downregulation of A1 AR and PPARα. [ABSTRACT FROM AUTHOR]