title: Captopril and ramiprilat protect against free radical injury in isolated working rat hearts.
abstract: The protection of angiotensin converting enzyme (ACE) inhibitors, captopril and ramiprilat, against free radical-mediated myocardial injury were studied in isolated working rat hearts. Free radicals were generated by electrolysis of Krebs-Henseleit solution with 10 mA direct current for 1 min. Both captopril (360 mumol/l) and ramiprilat (12.5 mumol/l) significantly reduced the decrease of left ventricle dP/dt'max, coronary flow (CF), myocardial superoxide dismutase (SOD) and creatine kinase (CK) activities and the elevation of S-T segment of epicardial ECG as well as the rise of myocardial malondialdehyde (MDA) content caused by electrolysed perfusate. Captopril afforded a dose-dependent protection on cardiac functions with various concentrations of 45, 90, 180 and 360 mumol/l. Iloprost (30 nmol/l), a stable mimetic of prostacyclin, could also alleviate free radical-mediated myocardial injuries. All the beneficial effects of ramiprilat (12.5 mumol/l) were abolished by the administration of indomethacin (5 mumol). In contrast, captopril (90 mumol/l) still exhibited significant protective effects after indomethacin (9 mumol) was administered, though these protective effects were insignificantly weakened. In order to assess the role of sulfhydryl (-SH) group in the effects of captopril, a SH-containing drug S8 and a disulfide DG4, both are deficient in ACE inhibitory properties in vitro, were examined. Data showed that S8 (180 mumol/l) provided a significant protection while DG4 showed no protective effect. It is concluded that ACE inhibitors can protect against free radical-induced myocardial damage. Ramiprilat, a non-SH-containing ACE inhibitor, inhibits free radical-induced damages mainly by stimulation of prostacyclin synthesis and/or release. In addition to this effect, captopril, a SH-containing ACE inhibitor, may exert additional anti-free radical effects by a mechanism which is probably related to the sulfhydryl group.
authors.affiliation: Department of Pharmacology, Hunan Medical University, Changhsa, People's Republic of China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Pi
authors.forename: X
authors.initials: X
authors.lastname: Chen
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D005609:Free Radicals; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology*; D017257:Ramipril / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004220:Disulfides; D005609:Free Radicals; D011758:Pyrroles; D013438:Sulfhydryl Compounds; C052549:ramiprilat; D002216:Captopril; D017257:Ramipril; D007213:Indomethacin; D004121:Dimethyl Sulfoxide