We assessed the inhibitory effect of UP269-6, a new orally active angiotensin II (ANG II) receptor antagonist, on the pressor action of exogenous ANG I in healthy male volunteers maintained on an unrestricted sodium intake and compared it with that of enalapril. Seven different single doses of UP269-6 ranging from 5 to 180 mg, 20 mg enalapril, or placebo were administered to 16 subjects in a double-blind fashion. The order of placebo and enalapril was randomized, and UP269-6 was given in an ascending dose order. The peak systolic blood pressure (SBP) response to a test dose of ANG I was determined serially before and after oral drug administration by monitoring finger BP by a photoplethysmographic method. No drug-related side effect was observed. There was a dose-dependent inhibition of the SBP response to the ANG I challenge. Doses as low as 40 to 80 mg had blocking effects quite similar to that of enalapril 20 mg. Ten hours after the 20- and 40-mg doses of UP269-6, the SBP response was still attenuated when drug levels no longer were measurable in plasma. UP269-6 also produced a dose-related increase in active renin and ANG II levels at 24 h after drug intake. In these volunteers on unrestricted salt intake, no statistically significant effect on 24-h urinary aldosterone excretion was observed. Based on these preliminary data, the pharmacokinetic drug half-life (t 1/2) was estimated at 4.7 h and the EC50 was estimated at 41 ng/ml. UP269-6 appears to be a well-tolerated, potent, orally active, antagonist of ANG II receptors in men. Doses of 40-80 mg might block the ANG I pressor response as does enalapril 20 mg.