title: Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals?
abstract: The abilities of angiotensin converting-enzyme (ACE) inhibitors to suppress superoxide anion formation in vitro and to improve postischemic cardiac function in vivo were examined. Three sulfhydryl-containing ACE inhibitors, captopril, its stereoisomer SQ 14,534, and an analog, zofenopril (SQ 26,703) were compared with enalaprilat and teprotide, which lack the sulfhydryl group but inhibit ACE, and two compounds, N-2-mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC), which contain a thiol moiety but are not ACE inhibitors, for suppression of free radical formation in vitro. The autooxidation of epinephrine to adrenochrome is mediated by superoxide anions and inhibited by captopril, SQ 14,534, and zofenopril, with similar IC50 values of 8 to 10 microM, but not by enalaprilat or teprotide (IC50 greater than 1000 microM). This reaction is also inhibited by MPG and NAC with IC50 values of 19 and 17 microM, respectively. In addition, captopril, MPG, or NAC, but not teprotide or enalaprilat, scavenge superoxide anion production by the purine-xanthine oxidase reaction and by canine neutrophils activated with phorbol myristate acetate. These results indicate that captopril scavenges superoxide anions in vitro independent of an action on ACE, which is probably related to the presence of a sulfhydryl moiety. Myocardial segmental function in the anesthetized, open-chest dog is altered during ischemia from active shortening to passive lengthening. Reperfusion after 15 min of ischemia does not restore active shortening within a 3 hr experimental period. Pretreatment of dogs with captopril intravenously (5 mg/kg) results in a 40% to 60% return to active shortening within 60 min of reperfusion. In contrast, equihypotensive doses of enalaprilat do not improve segmental function during reperfusion. Dogs given captopril immediately before restoring coronary blood flow show a similar return of function as that observed in animals treated with the drug before occlusion. SQ 14,534, the isomer of captopril, which is 100-fold less potent as an ACE inhibitor but equipotent in scavenging superoxide anions, also improves reperfusion-induced cardiac dysfunction when administered at reperfusion (5 mg/kg). Thus captopril improves postischemic contractile derangements by a mechanism independent of ACE inhibition. Restoration of blood supply to the ischemic myocardium provokes ventricular fibrillation in 37.5% of control dogs but in only 9% of those administered enalaprilat and 0% of captopril-treated animals. SQ 14,534 does not reduce the incidence of ventricular fibrillation (40%), indicating that the antifibrillatory actions may be related to ACE inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla.
authors.forename: W
authors.initials: W
authors.lastname: Westlin
authors.forename: K
authors.initials: K
authors.lastname: Mullane
mesh_terms: D000323:Adrenochrome / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology; D002216:Captopril / Q000031:analogs & derivatives / Q000494:pharmacology*; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000378:metabolism; D005609:Free Radicals; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010477:Perfusion; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D005609:Free Radicals; D013438:Sulfhydryl Compounds; D013481:Superoxides; D000323:Adrenochrome; D002216:Captopril; D013755:Tetradecanoylphorbol Acetate; D004837:Epinephrine