High-salt intake can change the effect of adenosine on arterial tone in mice. The aim of this study was to clarify the mechanism by which this occurs. Using aortas from mice fed a 4% NaCl (HS) or 0.45% NaCl (NS) diet for 4-5 wks, concentration-response curves for ACh, 5'-N-ethylcarboxamidoadenosine (NECA; adenosine analog) and 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride hydrate [CGS-21680; A(2A) adenosine receptor (A(2A) AR) agonist] were obtained with N(omega)-nitro-L-arginine methyl ester (L-NAME; nitric oxide inhibitor, 10(-4) M), methylsulfonyl-propargyloxyphenylhexanamide [MS-PPOH; a CYP (cytochrome P-450) epoxygenase blocker, 10(-5) M including CYP2J2], 12-(3-adamantan-1-yl-ureido)dodecanoic acid [AUDA; soluble epoxide hydrolase (sEH) blocker, 10(-5) M], dibromo-dodecenyl-methylsulfimide [DDMS; CYP omega-hydroxylase (CYP4A blocker), 10(-5) M], glibenclamide (K(ATP) channel blocker; 10(-5) M) and 5-hydroxydecanoate (5-HD; mitochondrial-K(ATP) channel blocker, 10(-4) M). HS dose response to ACh (10(-7) - 10(-5) M) was not different from NS (P > 0.05). Relaxation to 10(-6) M NECA was greater in the HS group (28.4 +/- 3.9%) than in the NS group (4.1 +/- 2.3%). Relaxation to 10(-6) M CGS-21680 was also greater in HS (27.9 +/- 4.5%) than in NS (4.9 +/- 2.2%). L-NAME was able to block the dose response of ACh (10(-7) - 10(-5) M) equally in both HS and NS (P > 0.05), whereas L-NAME did not block CGS-21680-induced response in HS. In HS the CGS-21680 response was greatly reduced by MS-PPOH (to 4.7 +/- 2.0%) and 5-HD (to 8.9 +/- 2.2%), and also abolished by glibenclamide (-1.0 +/- 5.9%). In NS, the CGS-21680 response was increased by AUDA (to 26.3 +/- 3.4%) and DDMS (to 27.2 +/- 3.0%). Compared with NS, HS vessels showed increased CYP2J2 and A(2A) AR expression (46 and 74% higher, respectively) but decreased sEH, CYP4A, and A(1) AR expression (75, 30, and 55% lower, respectively). These data suggest that in mice fed NS-containing diet, upregulation of arterial A(1) receptor causes vasoconstriction via increased sEH and CYP4A proteins. However, in mice fed HS-containing diet, upregulation of A(2A) receptor protein triggers vascular relaxation through ATP-sensitive (K(+)) channels via upregulation of CYP2J2 enzyme.