We have previously found that vascular receptors for atrial natriuretic peptide (ANP) in the rat are down-regulated by volume expansion. For this reason vascular ANP receptor density and affinity were examined in a model of volume-expanded hypertension, the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. The density of mesenteric vascular ANP binding sites was decreased in DOCA-salt hypertensive rats from a control value in uninephrectomized rats of 203 +/- 25 fmol/mg protein to 60 +/- 13 fmol/mg protein (p less than 0.01). The sensitivity of norepinephrine-precontracted aorta to ANP was significantly reduced in DOCA-salt hypertensive rats (p less than 0.001). DOCA-salt hypertensive rats infused intravenously for 4 days with ANP, 100 to 300 ng/hr, did not experience a lowering of blood pressure, in contrast to the significant reduction in blood pressure seen in two-kidney, one clip Goldblatt hypertensive rats similarly infused. In the latter there was no natriuretic response to ANP, while in the DOCA-salt hypertensive rats natriuresis occurred without lowering of blood pressure. In the DOCA-salt hypertensive rats plasma ANP concentration was increased to 68 +/- 8 fmol/ml from 10 +/- 1 fmol/ml in uninephrectomized rats. In conclusion, raised ANP concentration in plasma of volume-expanded hypertensive rats (DOCA-salt hypertension) may result in decreased density of ANP vascular receptors. These results suggest that a decrement in the number of ANP receptors may be a cause of decreased sensitivity of vascular responses to ANP in vitro and resistance to the blood pressure-lowering action of ANP in vivo.