Cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) dilate rat preglomerular microvessels when adenosine _2A receptors (A_2AR) are stimulated. As high salt (HS) intake increases epoxygenase activity and adenosine levels, we hypothesized that renal adenosine responses would be greater in HS-fed rats. Male Sprague-Dawley rats were fed either HS (4.0% NaCl) or normal salt (NS; 0.4% NaCl) diet. On day 8, isolated kidneys were perfused with Krebs' buffer containing indomethacin (10µM) and L-NAME (200µM) and preconstricted to ca 150 mm Hg with infusion of phenylephrine (10^-7M). Renal effluents were extracted for analysis of eicosanoids by GC/MS. Bolus injections of the stable adenosine analog 2-chloroadenosine (2-CA; 0.1-10µg) resulted in dose-dependent dilation; at 10µg, perfusion pressure (PP) was lowered to a greater extent in the kidneys of HS rats compared to NS rats (-60±4 mm Hg vs. -31±8 mm Hg; p<0.05) and the area of response was increased (27±6 mm² vs. 9±4 mm²; p<0.05), as was EET release (132±23 ng vs. 38±18 ng; p<0.05). HS treatment increased A_2AR and CYP2C23 protein expression. A selective epoxygenase inhibitor, MS-PPOH (12 µM), significantly reduced the response to 2-CA in HS rats; PP, area of response, and EET release decreased by 40%, 70% and 81%, respectively, whereas lesser changes were evident in NS kidneys. Thus, the greater vasodilator response to 2-CA seen in kidneys obtained from HS-fed rats was mediated by increased EET release. As EETs are renal vasodilator and natriuretic eicosanoids, interactions between adenosine and EETs may contribute to the adaptive response to HS intake.