Differential influences of angiotensin converting-enzyme inhibitors on the coronary circulation.
The effects of captopril and zofenoprilate (the active form of the prodrug zofenopril and also a sulfhydryl-containing angiotension converting-enzyme inhibitor) on coronary flow in the isolated rat heart were compared with the effects of a nonsulfhydryl converting-enzyme inhibitor, ramiprilate (the active form of the prodrug ramipril) and of sulfhydryl-containing compounds with no converting-enzyme inhibiting properties such as glutathione, cysteine, and the (R,S)-isomer of captopril. Drug concentrations of the angiotensin converting-enzyme inhibitors were equipotent in their effect on angiotensin I pressor response. Concentrations of the other compounds were equimolar with respect to the sulfhydryl group. Hearts treated with captopril, its isomer, zofenoprilate, cysteine, and glutathione showed significant increases in coronary flow by 5 min of perfusion. In contrast, ramiprilate treatment resulted in a slower increase in coronary flow that was only significant after 20 min of perfusion. The effect of ramiprilate was associated with a significant increase in 6-keto-prostaglandin (PG) F1 alpha overflow in the coronary effluent compared with that in saline-treated hearts, whereas captopril and glutathione had no significant effect on overflow of the measured cyclooxygenase products 6-keto-PGF1 alpha, thromboxane B2, and PGE2. The effects of captopril, zofenoprilate, and glutathione on coronary flow were dose dependent. These results corroborate the view that ramiprilate enhances coronary flow by affecting prostacyclin synthesis, mediated by an increase of endogenous bradykinin.(ABSTRACT TRUNCATED AT 250 WORDS)
van Gilst
W H
WH
Department of Pharmacology/Clinical Pharmacology, University of Groningen, The Netherlands.
Scholtens
E
E
de Graeff
P A
PA
de Langen
C D
CD
Wesseling
H
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D003327:Coronary Disease / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013318:Stroke Volume / Q000187:drug effects; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013599:Systole / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D002216:Captopril