Adenosine plays a critical role in the regulation of renal vascular tone and tubular function (1). Stimulation of adenosine _2A receptor (A_2AR) in rat preglomerular microvessels (PGMV) is linked to production of epoxyeicosatrienoic acids (EETs) and 11,12-EET was identified as the likely candidate mediator of PGMV dilatation on activation of the A_2AR (2). We also showed that in rat PGMV, EETs stimulate mono-ADP ribosyltransferase resulting in Gs_α activation and subsequent activation of adenylyl cyclase and K⁺_Ca2+ channel activity (3). EETs are important modulators of cardiovascular function as they exhibit vasodilation and natriuretic properties (4). Increase in EETs is a significant component of the kidney’s adaptive response to prevent blood pressure (BP) elevation in response to high salt (HS) intake. As adenosine levels are increased by salt intake and mice lacking A_2AR exhibit elevated BP, we proposed that adenosine is the stimulus for increased epoxygenase activity in response to HS. In male Sprague-Dawley (SD) rats fed HS (4.0% NaCl) or normal salt (NS; 0.4% NaCl) diet for 7 days, renovascular responses to 2-chloroadenosine (2-CA; 10µg) were augmented and renal protein expression of A_2AR induced in HS fed rats (5). These changes were associated with a 5-fold upregulation of CYP2C23 protein, a salt-inducible epoxygenase, and a 3-fold increase in the renal efflux of EETs and dihydroxyeicosatrienoic acids (DHTs). The responses to 2-CA were unaffected by inhibition of nitric oxide (NO) synthase or cyclooxygenases with L-NAME (200µM) and indomethacin (10µM), respectively, but a selective epoxygenase inhibitor, N-methylsulfonyl (propargyloxyphenyl) hexanamide (MS-PPOH; 12 µM), significantly reduced the response to 2-CA in HS rats, whereas lesser changes were evident in NS kidneys. We then examined the role of the A_2AR-EET pathway in Dahl salt sensitive (DS) rats, a genetic model of salt-dependent hypertension. When male DS rats were fed NS or HS (8.0% NaCl) diet, BP increased from 124±3 to 167±2mmHg in HS-fed rats (p<0.05). Compared to SD rats, kidneys of DS rats exhibit reduced sensitivity to 2-CA, as reflected by a rightward shift in the dose-response (D-R) curve (IC₅₀ 0.47µg vs. 7.26µg in SD and DS rats, respectively; p<0.05). Responses to 2-CA in DS rats were decreased by L-NAME, but not by MS-PPOH nor indomethacin. The D-R curve to 2-CA was similar in DS rats fed a NS or HS diet, as was renal efflux of EETs+DHTs (54.5±8.3 vs. 70.5±4.7 ng in response to 50µg 2-CA, respectively). HS intake in DS rats failed to upregulate renal protein expression of A_2AR and CYP2C23. Thus, NO, not EETs, is the key mediator of 2-CA-induced dilation in DS rats. Thus, the A_2AR-EET pathway mediates the renal protective effects of adenosine and an inability to upregulate this pathway may contribute to the development of salt-induced hypertension.