Nephrotic syndrome is associated with resistance to the renal actions of atrial natriuretic peptide (ANP). We performed experiments in anesthetized, acutely nephrectomized rats 21-28 days after injection of adriamycin (7-8 mg/kg iv) or 9-14 days after injection of anti-Fx1A antiserum (5 ml/kg ip) (passive Heymann nephritis; PHN) to test whether extrarenal resistance also occurred. Proteinuria was significantly elevated in both models compared with controls before study. ANP infusion (1 µg · kg¹ · min¹) caused arterial pressure to decrease similarly in control rats, adriamycin-treated rats, and rats with PHN (by 8.2 ± 1.0, 9.4 ± 2.3, and 9.0 ± 2.0%, respectively; all P < 0.05 vs. both baseline and vehicle-infused control rats). In control rats, hematocrit increased progressively to a maximal value 9.5 ± 0.9% over baseline as a result of the infusion, an increase corresponding to a reduction in plasma volume of 16.1 ± 0.9%. The ANP-induced increase in hematocrit was preserved in adriamycin-treated rats (9.2 ± 1.3%) but was markedly blunted in rats with PHN (2.4 ± 1.3%; P < 0.0001 vs. ANP infusion in control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate was significantly lower in rats with PHN compared with both control and adriamycin-treated rats. Infusion of a subpressor dose of angiotensin II (ANG II, 2.5 ng · kg¹ · min¹) fully restored the ANP-induced increase in hematocrit in rats with PHN. This study demonstrates that 1) the hemoconcentrating and hypotensive actions of ANP are preserved in adriamycin-treated rats, 2) the effect of ANP on hematocrit and fluid distribution is blunted in rats with PHN while its hypotensive action is preserved, and 3) low-level ANG II infusion normalizes the hemoconcentrating effect of exogenously infused ANP in rats with PHN. Thus deficient ANG II generation in rats with PHN, but not adriamycin nephrosis, may contribute to extrarenal ANP resistance.