The cardiovascular effects of a novel enkephalin analogue, 443C81 (Tyr-D-Arg-Gly-Phe(4NO2)-Pro.NH2), were studied in healthy volunteers. According to a double-blind, cross-over, randomised, balanced design, six men received two different doses of 443C81 or saline as intravenous (i.v.) infusions on three occasions. Mean +/- SD plasma concentrations achieved at steady state were 0.46 +/- 0.11 microgram/ml after low-dose 443C81 and 1.0 +/- 0.2 microgram/ml after high-dose 443C81. In the supine position, low and high doses produced mean transient increases in diastolic blood pressure (DBP) of 5 and 4 mm Hg and heart rate (HR) of 5 and 12 beats/min, respectively. With the higher dose, these changes were followed by a mean decrease in DBP of 8 mm Hg while HR returned to control values. When the subjects were tilted, the pressor effect was not observed, and hypotension occurred earlier and was more pronounced. Both doses reduced forearm and systemic vascular resistance, and there was a dose-related increase in supine forearm venous capacitance; venoconstriction associated with tilting was unaffected by 443C81. Plasma renin activity and elevation of epinephrine concentrations on tilting were increased by the enkephalin, which also caused a diuresis through an increase in free water clearance.