Correlation between anti-hypertensive activity in rats and plasma angiotensin I-converting enzyme (ACE) inhibition in mice following oral administration of ACE inhibitors.
Thirty-four ACE inhibitors were evaluated to determine the concentration giving 50% inhibition of purified rabbit lung ACE (IC50 microM) using benzyloxycarboxyl-p-NO2-Phe-His-Leu as substrate, to determine the oral dose causing a lowering in blood pressure of 30 mm Hg (ED30 mumol/kg) in acute aortic coarctate (AAC) rats, and to determine inhibition of plasma ACE (PACE) activity in mice after oral dosing. Mouse PACE activity was determined with 14C-Hip-His-Leu as substrate one hour after oral dosing of 3 animals/group with 5 or 50 mumol ACE inhibitor per kg. Data from mice were expressed as percent of control group PACE activity. Least squares regression analysis showed the IC50 data to be poorly correlated with either rat data or mouse PACE data at 50 mumol/kg p.o. However, correlation was significant between log rat ED30 and mouse PACE at 5 (p less than 0.001, r = 0.570) and 50 (p less than 0.025, r = 0.387) mumol/kg p.o. Thus, the simple mouse plasma ACE determination after a dose of 5 mumol/kg is a convenient supplement to the AAC rat model for showing oral activity of ACE inhibitors.
Pong
S F
SF
Brooks
R R
RR
Huang
C T
CT
Moore
A F
AF
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004656:Enalapril; D006977:Hypertension, Renal / Q000503:physiopathology; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D011817:Rabbits; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004151:Dipeptides; D004656:Enalapril; D002216:Captopril; D007703:Peptidyl-Dipeptidase A