Cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) dilate rat preglomerular microvessels (PGMVs) when adenosine 2A receptors (A(2A)R) are stimulated. As high salt intake increases epoxygenase activity and adenosine levels, we hypothesized that renal adenosine responses would be greater in high salt-fed rats. We have obtained evidence supporting this hypothesis in rats fed a high salt diet for 7 days. Stimulation of adenosine receptors with 2-chloroadenosine in kidneys obtained from rats on high salt (4%) intake produced an increase in EET release that was several-fold greater than in kidneys of rats on normal salt (0.4% NaCl) diets, which was associated with a sharp decline in renovascular resistance. Under conditions of high salt intake, an associated upregulation of A(2A)R and 2C23 protein expression was observed. As EETs are renal vasodilator and natriuretic eicosanoids, the antipressor response to salt loading may operate through an A(2A)R - EET mechanism. These findings expand the role of adenosine-related mechanisms in protecting renal function.