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To assess clearance mechanisms of atrial and brain natriuretic peptides in the circulation, we examined the effects of a neutral endopeptidase (NEP) inhibitor and a clearance receptor ligand on plasma concentrations of the peptides in normal rats. Plasma concentrations of endogenous α-rat atrial natriuretic peptide (α-rANP) were not significantly elevated by intravenous infusion of a NEP inhibitor, phosphoramidon, but were elevated threefold by intravenous infusion of a clearance receptor ligand, des(Gln18-Gly22)-rANP(4−23)-NH2 [C-ANF(4−23)]. On the other hand, the clearance of α-rANP given intravenously at the pharmacological dose, 600 pmol/ min/kg for 2 min, was decreased to one-third by the administration of phosphoramidon, although the administration of C-ANF(4−23) did not significantly decrease the clearance. The clearance of rat brain natriuretic peptide (rBNP) given at 600 pmol/min/kg for 2 min was approximately 38% lower than that of α-rANP. The effect of phosphoramidon on the clearance of rBNP was not significant and was similar to that of C-ANF(4−23). These results suggest that clearance receptor is involved in the clearance of the physiological levels of α-rANP and that NEP plays a major role in the clearance of a pharmacological dose of α-rANP, at which clearance receptors are thought to be saturated, and also indicate a pharmacokinetic difference between α-rANP and rBNP.