Plasma Angiotensin I Determines the Rate of Angiotensin II Generation Even during ACE Inhibition

ABSTRACT

After single or multiple administration of an angiotensin converting enzyme(ACE) inhibitor, plasma angiotensin(ANG) II recovers more rapidly than plasma ACE-activity. To investigate the dynamics of the biochemical changes induced by ACE inhibition, 6 normal volunteers received in a randomized order one dose of enalapril (E, 20mg), an ACE-inhibitor with a 35 hour terminal half-life, or benazepril (B, 20 mg), an ACE-inhibitor with a 23 hour terminal half-life. Biochemical effects of the 2 agents were compared at 0-4 hours and 14-30 hours after drug intake. ACE-inhibition was estimated in vivc by the ratio between plasma ANG II and blood ANG I (ANG II/ANG I) and in vitro by a radioenzymatic assay. At peak inhibition (4 hours after E, 2 hours after B), plasma ACE-activity was inhibited with E by 94% in vivo and by 98% in vitro, compared to 98% and 97%, respectively, with B. Twenty-four hours post drug, plasma ACE-activity was inhibited with E by 84% in vivo and by 83% in vitro, compared to 64% and 94%, respectively, with B. Plasma ACE-inhibition largely exceeded 24 hours and was independent of terminal half-lives. ANG II levels were initially suppressed by 88% with E and by 95% with B, but they returned to their initial values within 24 hours. Active renin measured by IRMA was increased to 183% and 313% 4 and 24 hours after E, and to 342% and 337% after B. Corresponding ANG I levels were 240% and 319% for E, and 329% and 295% for B; they were highly correlated to active renin (r=0.82, n=252, p<0.001). Thus, 24 hours post-drug, ANG II/ANG I was still reduced but the biologically effective product of the renin-angiotensin system(RAS), ANG II, has returned to its initial level, as a consequence of the increase in renin secretion and ANG I production. The RAS is reset at a time when ACE-inhibition is still effective. Feed-back increase in renin release seems to be an important factor contributing to the reappearance of ANG II in plasma in the presence of ACE-inhibition.