1. The aim of the present study was to determine whether the vasorelaxant effect of atrial natriuretic peptide (ANP) is, in part, endothelium dependent in humans. 2. We used veno-occlusive plethysmography to measure forearm blood flow (FBF) during intra-arterial infusions of ANP (4, 8, 16, 32 pmol/min per dL forearm tissue volume) before and after the inhibition of nitric oxide (NO) synthesis by N(G)-monomethyl-L-arginine (L-NMMA; 100 micromol) in seven normal healthy subjects. 3. Atrial natriuretic peptide caused a dose-dependent increase in FBF both before and after L-NMMA and significantly reduced the plasma concentration of angiotensin (Ang) II. Administration of L-NMMA significantly diminished the increase in FBF in response to ANP infusion (P < 0.05). 4. These results suggest that the forearm vasodilative response to ANP is modulated, in part, by an endothelium-derived NO-mediated mechanism associated with a decrease in AngII caused by ANP.