To further study the mechanisms of the renal effects of ANP, we examined the effects of NaCl loading and ANP infusion on nephrogenous cGMP production. Six normotensives (NTs) and 7 essential hypertensives (HTs) were placed on 7-day low (3 g/day) and then 7-day high NaCl diets (20 g/day). On the last day of each period, the natriuretic and nephrogenous cGMP responses to ANP infusion at 25 ng/kg/min for 40 min were determined. ANP infusion markedly increased the plasma concentrations of ANP and cGMP and the urinary excretions of Na and cGMP. These changes were accompanied by a rise in nephrogenous cGMP. Increases in nephrogenous cGMP during ANP infusion were not different between HTs and NTs despite a greater natriuretic response in HTs. NaCl loading significantly increased the natriuretic response to ANP infusion in both groups. However, nephrogenous cGMP production induced by ANP infusion was not affected by changes in NaCl intake. Thus, although ANP-induced natriuresis is associated with an increase in nephrogenous cGMP, the natriuretic effect of ANP seems to be modified to a greater extent by indirect mechanisms such as renal perfusion pressure and body fluid volume status.