Salt modulates vascular response through adenosine A_2A receptor in eNOS-null mice: Role of CYP450 epoxygenase and soluble epoxide hydrolase

High salt (HS) intake can change the arterial tone in mice, and the nitric oxide (NO) acts as a mediator to some of the receptors mediated vascular response. The main aim of this study was to explore the mechanism behind adenosine-induced vascular response in HS-fed eNOS^+/+ and eNOS ^-/- mice The modulation of vascular response by HS was examined using aortas from mice (eNOS^+/+ and eNOS^-/-) fed 4% (HS) or 0.45% (NS) NaCl-diet through acetylcholine (ACh), NECA (adenosine-analog), CGS 21680 (A_2A AR-agonist), MS-PPOH (CYP epoxygenase-blocker; 10 ^-5 M), AUDA (sEH-blocker; 10^-5 M), and DDMS (CYP4A-blocker; 10^-5 M). ACh-response was greater in HS-eNOS ^+/+ (+59.3 ± 6.3%) versus NS-eNOS^+/+ (+33.3 ± 8.0%; P < 0.05). However, there was no response in both HS-eNOS ^-/- and NS-eNOS^-/-. NECA-response was greater in HS-eNOS^-/- (+37.4 ± 3.2%) versus NS-eNOS^-/- (+7.4.0 ± 3.8%; P < 0.05). CGS 21680-response was also greater in HS-eNOS^-/- (+45.4 ± 5.2%) versus NS-eNOS^-/-(+5.1 ± 5.0%; P < 0.05). In HS-eNOS^-/-, the CGS 21680-response was reduced by MS-PPOH (+7.3 ± 3.2%; P < 0.05). In NS-eNOS ^-/-, the CGS 21680-response was increased by AUDA (+38.2 ± 3.3%; P < 0.05) and DDMS (+30.1 ± 4.1%; P < 0.05). Compared to NS, HS increased CYP2J2 in eNOS^+/+ (35%; P < 0.05) and eNOS ^-/- (61%; P < 0.05), but decreased sEH in eNOS^+/+ (74%; P < 0.05) and eNOS^-/- (40%; P < 0.05). Similarly, CYP4A decreased in HS-eNOS^+/+ (35%; P < 0.05) and HS-eNOS^-/- (34%; P < 0.05). These data suggest that NS causes reduced-vasodilation in both eNOS^+/+ and eNOS^-/- via sEH and CYP4A. However, HS triggers possible A_2AAR-induced relaxation through CYP epoxygenase in both eNOS^+/+ and eNOS^-/-.