1. The present studies compare the early renal response to (a) an endopeptidase-24.11 (E-24.11) inhibitor (candoxatrilat) (b) an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) and (c) the combination of endopeptidase-24.11 and ACE inhibition in the rat A-V fistula model of chronic volume overload. 2. Candoxatrilat (3 and 10 mg kg-1) i.v. produced a prompt 3 fold increase in urinary sodium and cyclic GMP excretion without affecting significantly blood pressure or glomerular filtration rate (GFR). 3. Lisinopril (0.03 mg kg-1) alone inhibited the pressor response to angiotensin I but had no significant effect on urinary sodium excretion or blood pressure. 4. Lisinopril (0.03 mg kg-1) attenuated significantly the early natriuretic response to candoxatrilat (3 mg kg-1) and the associated rise in urinary cyclic GMP, but sodium excretion eventually reached levels associated with acute E-24.11 inhibition. 5. Doses of the dual E-24.11/ACE inhibitor, sampatrilat, that inhibited the pressor response to angiotensin I reduced mean arterial blood pressure and produced a delayed natriuresis and rise in urinary cyclic GMP excretion when compared to candoxatrilat alone. 6. Concurrent administration of an ACE inhibitor reduces the early renal response to E-24.11 inhibition in the A-V fistula rat, an effect attributable to the hypotensive action of this combination.