Nayeem_2013_Am.J.Physiol.Regul.Integr.Comp.Physiol_304_R23

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 A(2A) adenosine receptors (AR) via CYP-epoxygenases and peroxisome proliferator-activated receptor gamma (PPARgamma). sEH(-/-) showed an increase in A(2A) AR, CYP2J, and PPARgamma by 31%, 65%, and 36%, respectively, and a decrease in A(1)AR and PPARalpha (30% and 27%, respectively) vs. sEH(+/+). 5'-N-ethylcarboxamidoadenosine (NECA, an adenosine receptor agonist), CGS 21680 (A(2A) AR-agonist), and GW 7647 (PPARalpha-agonist)-induced responses were tested with nitro-l-arginine methyl ester (l-NAME) (NO-inhibitor; 10(-4) M), ZM-241385, SCH-58261 (A(2A) 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 muM) or trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB, sEH-inhibitors; 10(-5) M), and T0070907 (PPARgamma-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). PPARalpha-agonist did not relax as CGS 21680 (-2.48 +/- 1.1 vs. +37.4 +/- 5.4%) in sEH(-/-), and PPARgamma-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 A(2A) AR, CYP2J, and PPARgamma, and the downregulation of A(1) AR and PPARalpha.