Objective: Investigate the role of NO in the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in 2K1C model. Method: The endothelial NO synthase gene knockout mice and their wild-type controls were used. Renal concentrations of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) were measured in nonclipped kidney. Renal NO synthase activity was determined by measuring the rate of formation of L-[14 C]citruline. Results: Treatment with the sEH inhibitor caused the same BP decrease that was associated with increase in daily sodium excretion in both types of mice. The ratio of EETs/DHETEs in the nonclipped kidney was increased and did not alter renal NOS activity. sEH inhibition reduced significantly glomerular and tubulointestitial injury. Conclusion: BP-lowering effects of chronic sEH inhibition in 2K1C mice are associated with normalization of the reduced availability of biologically active EETs in the nonclipped kidney and their direct natriuretic actions.