We studied the effect of converting enzyme inhibition with enalapril on the natriuresis observed after administration of atrial natriuretic factor (human ANF-99–126], given as a 100-fig bolus i.v. injection) in eight healthy humans consuming a 100 mmol sodium diet. Without enalapril, sodium excretion rose from 127 ± 19 (mean ± SE) to 437 ± 103 μmol/min in the first 20 minutes after ANF was administered. Clearance studies performed during maximal water diuresis indicated a rise in glomerular filtration rate (inulin clearance), free water clearance, phosphate, lithium, uric acid, and magnesium excretion. Four days of enalapril (20 mg b.i.d.) increased effective renal plasma flow (p-aminohippurate clearance) and reduced blood pressure (from 114/71 ± 2/2 to 105/60 ± 2/1 mm Hg). Under these conditions baseline sodium excretion was not different from the control study, but it rose less after ANF (from 117 ± 22 to 242 ± 63 μmol/min), and the increments in glomerular nitration rate, free water clearance, phosphate, lithium, uric add, and magnesium were all blunted and nonsignificant. In addition, effective renal plasma flow tended to fall; this effect was not observed when ANF was given without enalapril. These results support the notion that the effects of ANF on renal hemodynamics and on tubular sodium handling depend on renal angiotensln II and that blood pressure reduction may interfere with the ANF-induced natriuresis.