We have re-examined digoxin-like immunoreactivity, commonly detected in plasma with antibodies, in order to determine whether it could represent the putative natriuretic factor originally proposed by de Wardener and Clarkson [1]. Experiments were conducted in adult rabbits with two-kidney, two wrapped hypertension and in shamoperated controls. Six weeks after the bilateral renal cellophane wrapping or sham operation, the mean arterial pressure (MAP) was approximately 40 mmHg higher in the wrapped group. At this time the rabbits started a low-, normal- or high-salt diet (1.6, 25.6 and 40.8 mmol Na+/100 g) which continued for 2 weeks. During the final 3 days urinary volume and total sodium content measured in 24-h collections was significantly lowered in the rabbits on the low-salt diet and increased by the high-salt diet (P< 0.01 for both). This pattern was identical for the normotensive and renal hypertensive rabbits. Digoxin-like immunoreactivity was measured at the beginning and at the end of the 2-week period of the salt study. Immediately before commencing the various salt diets the digoxin-like immunoreactivity, measured as ng digoxin equivalents/ml, was only marginally elevated in the renal hypertensive compared to the normotensive animals (it averaged 94.7 ± 7.7 and 80.9 ± 5.9 ng digoxin equivalents/ml, respectively). Neither the low- nor the high-sodium diet affected plasma digoxin-like immunoreactivity in either the normotensive or the renal hypertensive animals (P> 0.10). These results indicate that digoxin-like immunoreactivity is present in the plasma of normotensive and renal hypertensive rabbits. The lack of effect of alterations in dietary sodium intake, particularly in the renal hypertensive group (a model of hypertension with impaired renal function), indicates that the digoxin-like immunoreactivity may not represent the putative natriuretic hormone