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Digitalis glycosides exert both excitatory and inhibitory autonomic actions in animals and produce vasoconstriction in normal humans but produce vasodilation in heart failure patients. To determine whether or not these contrasting vascular responses are due to differing autonomic actions of the drug, we compared the responses to intravenous administration of Cedilanid-D (0.02 mg/kg) in eight normal subjects (mean age, 23 +/- 1 years) and eight patients with moderate-to-severe heart failure (mean age, 52 +/- 5 years, NYHA Class III-IV). Hemodynamics and efferent sympathetic nerve activity to muscle (MSNA) were measured during 5-minute periods before (control) and 20 minutes after drug administration. In the heart failure patients, Cedilanid-D significantly increased systolic and pulse pressures, whereas mean arterial pressure was unchanged. There was a decrease in right atrial pressure and a tendency for a decrease in pulmonary artery diastolic pressure with a slowing of heart rate. Cardiac index increased by 24 +/- 7%. Short-term administration of digitalis in these heart failure patients produced a fall in forearm vascular resistance (from 37.6 +/- 8.2 to 31.8 +/- 8.1 units, p less than 0.05) and an early, profound, and sustained decrease in MSNA (from 831.0 +/- 118.4 to 474.4 +/- 103.6 units/100 heart beats, p less than 0.01). Digitalis glycosides produced different vascular and MSNA responses in the normal subjects. In the normal volunteers, the drug significantly increased systolic, mean, and pulse pressures and decreased central venous pressure and heart rate. Despite the significant increase in arterial pressure, there was no change in forearm vascular resistance (from 11.7 +/- 1.0 to 12.7 +/- 1.0 units, p = NS) or MSNA (from 494.8 +/- 88.5 to 369.1 +/- 60.5 units/100 heart beats, p = NS), suggesting a sympathoexcitatory response in normal subjects. To determine whether or not the digitalis-induced sympathoinhibition in the heart failure patients was simply due to an inotropic effect (stimulation of inhibitory cardiac mechanoreceptors), we studied the responses of seven additional patients with heart failure before and during administration of dobutamine (3.4 +/- 0.4 micrograms/kg/min). Dobutamine produced a 34 +/- 3% increase in cardiac index, no significant change in systemic arterial pressures, a decrease in pulmonary artery diastolic and right atrial pressures, and no change in heart rate or forearm vascular resistance (from 30.2 +/- 4.3 to 26.5 +/- 4.7 units, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)