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Inhibitors of bradykinin (BK)-inactivating enzymes protect from myocardial ischemia/reperfusion injury after short periods of reperfusion. However, protection after 2 to 3 h of reperfusion does not mean that myocardium remains viable for an extended time. Therefore, we examined the effects of inhibitors of angiotensin-converting enzyme (ramiprilat), EP24.11 (cFP-F-pAB), and EP24.15 (cFP-AAF-pAB) in a chronic model of myocardial ischemia/reperfusion injury. A left descending coronary artery was occluded for 30 min in anesthetized rabbits. Saline, ramiprilat, or endopeptidase inhibitors were given after 27 min of occlusion. The BK(2) receptor antagonist HOE140 was administered in certain experiments. After ischemia, the occlusion was released, and the animal allowed to recover for 3 or 7 days. Surgery was then repeated, and the heart removed for determination of infarct size. In separate experiments, the heart was removed after 2 h of reperfusion for determination of BK tissue levels. Ramiprilat and endopeptidase inhibitors reduced infarct size at 3 and 7 days. Combining inhibitors further reduced infarct size after 3 days. The protective effect of the endopeptidase inhibitors was blocked by HOE140. Infarct sizes at 7 days were larger than at 3 days. The additive effect of multiple inhibitors was absent at 7 days. Ramiprilat and cFP-F-pAB significantly increased tissue BK levels. We conclude that inhibition of BK-inactivating enzymes protects endogenous BK from degradation and provides long-lasting protection from myocardial ischemia/reperfusion injury. A single treatment at the time of reperfusion does not prevent extension of the infarction between 3 and 7 days.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11504792&dopt=Abstract
Circulation. 1988 Jun;77(6 Pt 2):I24-9.
Differential influences of angiotensin converting-enzyme inhibitors on the coronary circulation.
van Gilst WH, Scholtens E, de Graeff PA, de Langen CD, Wesseling H.
Department of Pharmacology/Clinical Pharmacology, University of Groningen, The Netherlands.
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)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3286044&dopt=Abstract
Diabetologia. 2001 Jul;44(7):878-82.
Podocyte foot process broadening in experimental diabetic nephropathy: amelioration with renin-angiotensin blockade.
Mifsud SA, Allen TJ, Bertram JF, Hulthen UL, Kelly DJ, Cooper ME, Wilkinson-Berka JL, Gilbert RE.
Department of Physiology, University of Melbourne, Victoria, Australia.
AIMS/HYPOTHESIS: Changes in podocyte number and morphology have been implicated in the pathogenesis of proteinuria and the progression of human and experimental kidney disease. This study sought to examine podocyte foot process and slit pore architecture in experimental diabetic nephropathy and to determine whether such changes were modified with renoprotective intervention by blockade of the renin-angiotensin system. METHODS: The number of filtration slits per 100 microm of glomerular basement membrane was assessed by transmission electron microscopy and quantitated histomorphometrically in control animals and in rats with 24 weeks of streptozotocin-induced diabetes. Diabetic rats were either untreated or received the angiotensin converting enzyme inhibitor ramipril, or the angiotensin II type 1 receptor antagonist, valsartan. RESULTS: When compared with control animals, diabetes was associated with a decrease in the number of slit pores per unit length of glomerular basement membrane, indicative of podocyte foot process broadening. Both ramipril and valsartan attenuated these ultrastructural changes to a similar degree. These differences remained after correcting for glomerular volume as a possible confounding variable. CONCLUSION/INTERPRETATION: Preservation of podocyte architecture could contribute to the renoprotective effects of renin-angiotensin system blockade in diabetic nephropathy.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11508273&dopt=Abstract
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