Determinants of angiotensin II generation during converting enzyme inhibition.
The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.
Juillerat
L
L
Hypertension Division, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Nussberger
J
J
Ménard
J
J
Mooser
V
V
Christen
Y
Y
Waeber
B
B
Graf
P
P
Brunner
H R
HR
D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000096:biosynthesis* / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin