Differential inhibition of plasma versus tissue ACE by utibapril: biochemical and functional evidence for inhibition of vascular ACE activity.
Utibapril is an angiotensin-converting enzyme (ACE) inhibitor with a proposed tissue-specific inhibitory profile. This implies that at a certain dose, utibapril should be able to inhibit tissue ACE activity without affecting plasma ACE. Moreover, if tissue ACE activity is rate limiting, functional conversion of angiotensin I should be decreased. Accordingly, we studied the dose-dependent effect of long-term treatment with utibapril on plasma and tissue ACE. Normal Wistar rats were randomly allocated to oral treatment with different doses of utibapril (0, 2, 10, 50, or 250 micrograms/kg/day) for 30 days. Tissue inhibition of ACE was assessed biochemically, whereas functional conversion of angiotensin I was determined in the isolated organ. Utibapril significantly inhibited plasma, renal, and vascular ACE but not ventricular ACE activity. Notably, however, only treatment with the highest dose of utibapril resulted in a significant inhibition of plasma ACE, whereas vascular ACE activity was already significantly inhibited after treatment with a lower dose of utibapril. In accordance, utibapril dose-dependently inhibited the contraction of isolated aortic rings to angiotensin I. Furthermore, angiotensin I-induced decreases in coronary flow in the isolated heart were significantly inhibited after treatment with the higher doses of utibapril. These data suggest the preferential inhibition of vascular ACE by utibapril in normal rats. Furthermore, the dose-dependent inhibition of the functional conversion of angiotensin I indicates that the tissue ACE activity may be rate limiting in vascular beds in rats.
Buikema
H
H
Department of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands.
Pinto
Y M
YM
van Geel
P P
PP
Rooks
G
G
de Langen
C D
CD
de Graeff
P A
PA
van Gilst
W H
WH
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D003326:Coronary Circulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013830:Thiadiazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011355:Prodrugs; D013830:Thiadiazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C065021:utibapril; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A