We have recently demonstrated that intrarenal dopamine plays an important role in preventing the development of systemic hypertension. Similarly, renal cytochrome P450 (CYP)-epoxygenase-derived arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs) also are anti-hypertensive through inhibiting sodium reabsorption and vasodilation. The potential interaction between renal dopamine and epoxygenase systems was investigated. COMT^-/- mice with increased intrarenal dopamine levels and ptAADC^-/- with renal dopamine deficiency were treated with low-salt diet or high-salt diet for 2 weeks. Wild type or Cyp2c44^-/- mice were treated with gludopa, which selectively increased renal dopamine levels. In low-salt treated mice, urinary EET levels were related to renal dopamine levels, being highest in COMT^-/- mice and lowest in ptAADC^-/- mice. In high-salt treated mice, total EET and individual EET levels in both kidney and urine were also highest in COMT^-/- mice and lowest in ptAADC^-/- mice. Selective increases in renal dopamine in response to gludopa administration led to marked increases in both total and all individual EET levels in the kidney without any changes in blood levels. qRT-PCR and Western analysis indicated that gludopa increased renal Cyp2c44 mRNA and protein levels. Gludopa induced marked increases in urine volume and urinary sodium excretion in wild type mice. In contrast, gludopa did not induce significant increases in urine volume or urinary sodium excretion in Cyp2c44^-/- mice. These studies demonstrate that renal EET levels are maintained by intrarenal dopamine, and Cyp2c44-derived EETs play an important role in intrarenal dopamine-induced natriuresis and diuresis.