We hypothesize that A_2A adenosine receptors (A_2A AR) promote aortic relaxation in mice through CYP- epoxygenases, and help to avoid salt-sensitivity. Aortae from male mice maintained on a high salt diet (HS, 7% NaCl) or normal salt diet (NS, 0.45% NaCl) for 4-5 wks were used. Concentration-response curves (10^-11-10^-5 M) for NECA (non-selective adenosine analog) and CGS 21680 (A_2A AR agonist) were obtained with different antagonists including ZM 241385 (A_2A AR antagonist; 10^-6 M), SCH 58261 (A_2A AR antagonist; 10^-6 M), L-NAME (endothelial NOS inhibitor; 10^-4 M) and inhibitors including MS-PPOH (CYP epoxygenases inhibitor; 10^-5M), 14,15-EEZE, (EET antagonist; 10^-5M), DDMS (CYP4A inhibitor; 10^-5M) and HET0016 (20-HETE inhibitor; 10^-5M) . At 10^-7 M of NECA, significant relaxation in HS (+22.58 ± 3.12%) was observed compared to contraction in NS (-10.62 ± 6.27%, p<0.05). ZM-241385 changed the NECA response to contraction (p<0.05) in HS. At 10^-7 M of CGS 21680, significant relaxation in HS (+32.04 ± 3.08%) was observed compared to NS (+10.45 ± 1.34%, p<0.05). SCH 58261, L-NAME, MS-PPOH and 14,15-EEZE changed the CGS 21680-induced relaxation to contraction (p<0.05) in HS. Interestingly, DDMS and HET0016 changed CGS 21680 response to relaxation (p<0.05) in NS; however, there was no significant difference found between DDMS, HET0016-treated HS & NS vs. non-treated HS group (p>0.05). CYP2C29 protein was 55% and 74% up-regulated in HS vs. NS (p<0.05) mice aorta and kidney, respectively. CYP4A protein was 30.30% and 35.70% up-regulated in NS vs. HS (p<0.05) mice aorta and kidneys respectively. A₁ AR was down-regulated while A_2A AR was up-regulated in HS compared to NS. These data suggest that HS may activate CYP2C29 via A_2A AR, causing relaxation, whereas NS may contribute to the up-regulation of CYP4A causing contraction.