To determine whether the immune Fab fragment of digoxin antibody (digibind) attenuates established corticotropin (ACTH) hypertension, rats were given ACTH sham control (0.1 mL normal saline, twice daily, subcutaneously, n = 18) or ACTH treatment (2.5 microg/kg in 0.1 mL normal saline, twice daily, subcutaneously; n = 27) for 10 days. Acute hemodynamic effects of digibind (30 mg/kg, intravenous bolus injection) were examined after 10 days of sham control or ACTH treatment. Rats were divided into 7 groups: digibind (30 mg/kg, in 1 mL 0.9% NaCl intravenous bolus injection) plus sham (n = 6) or ACTH (n = 8), sham digibind (1 mL 0.9% NaCl intravenous bolus) plus ACTH (n = 7), digibind vehicle (sorbitol 1.8 mg in 1 mL 0.9% NaCl, intravenous bolus) plus sham (n = 6), preimmune sheep IgG (30 mg/kg in 1 mL 0.9% NaCl intravenous bolus) plus sham (n = 6) or ACTH (n = 6) and preimmune sheep IgG (Fab)2 fragment (30 mg/kg in 1 mL 0.9% NaCl intravenous bolus) plus ACTH (n = 6). ACTH increased systolic blood pressure (SBP) from 118 +/- 2 to 132 +/- 3 mm Hg on treatment day 10. BP was unchanged in sham treated rats. The acute administration of digibind decreased MAP (-14 +/- 3 mm Hg, P <.001) in ACTH hypertensive rats, but not in ACTH sham control normotensive rats (+2 +/- 3 mm Hg). Blood pressure reached a minimum after 14 +/- 3 min and the effect lasted more than 30 min. No significant change of blood pressure was found in ACTH treated rats receiving sham (0.9% NaCl) digibind injection (+2 +/- 2 mm Hg). However, both preimmune sheep IgG and IgG (Fab)2 fragment caused a decrease of blood pressure in both sham or ACTH treated rats. Although these data that digibind decreases BP in ACTH but not sham treated rats are consistent with the notion that digitalis-like substances may play a role in ACTH induced hypertension, the evidence that both preimmune sheep IgG and IgG (Fab)2 fragments also decreased blood pressure in rats suggests caution in interpretation of studies that employ digibind preparations.