It has been recently reported that intracoronary acetylstrophanthidin injection acutely sensitizes the cardiac baroreflex (vagal afferents). We wondered whether chronic administration of digoxin also augmented the gain of this reflex. We treated seven dogs with digoxin intravenously (40 micrograms/kg loading dose followed by 15 micrograms.kg-1.day-1) for 7 days; eight additional dogs received vehicle for 7 days. With the dogs under chloralose anesthesia, we assessed the changes in renal nerve activity that resulted from stimulation of cardiopulmonary receptors with volume expansion (15 ml/kg of 6% dextran in saline) in digoxin- and vehicle-treated groups under control conditions, after sinoaortic denervation (SAD), and after SAD plus vagotomy. Under control conditions volume expansion resulted in decreases of renal nerve activity of 13.5 +/- 3.5%/mmHg increase in pulmonary artery wedge pressure in digoxin-treated dogs. This tended to be greater than the response of sham-treated dogs (-9.5 +/- 1.5%/mmHg increase). After SAD, renal nerve activity decreased 19 +/- 5%/mmHg increase in pulmonary artery wedge pressure in the digoxin group compared with only 8 +/- 1%/mmHg increase in the vehicle group. These responses were significantly different. The plasma digoxin level in the digoxin-treated group was in the therapeutic range (1.9 +/- 0.4 ng/ml). Vagotomy abolished the responses to volume expansion in both groups. Thus chronic digoxin treatment resulting in therapeutic plasma levels of digoxin sensitizes vagal afferents mediating the cardiopulmonary baroreflex influence on renal nerve activity.