Comparison of the angiotensin II antagonist UP269-6 with the angiotensin converting enzyme inhibitor enalapril in normotensive volunteers challenged with angiotensin I.
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.
Inglessis
N
N
Hypertension Division, University Hospital, Lausanne, Switzerland.
Nussberger
J
J
Hagmann
M
M
Hiesse-Provost
O
O
Insuasty
J
J
Reid
J
J
Ménard
J
J
Brunner
H R
HR
D000284:Administration, Oral; D000328:Adult; D000450:Aldosterone / Q000652:urine; D000704:Analysis of Variance; D000803:Angiotensin I / Q000008:administration & dosage / Q000009:adverse effects*; D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004656:Enalapril / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010991:Plethysmography; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D011743:Pyrimidines; D013777:Tetrazoles; D000804:Angiotensin II; C088791:UP 269-6; D000450:Aldosterone; D004656:Enalapril; D000803:Angiotensin I; D012083:Renin