title: Reperfusion damage: free radicals mediate delayed membrane changes rather than early ventricular arrhythmias.
abstract: STUDY OBJECTIVE - The aim of the study was to reassess the role of reactive oxygen species in causing reperfusion arrhythmias, which they might do either by directly generating free oxygen radicals or by using scavengers of free oxygen radicals. DESIGN - Ventricular arrhythmias were studied in isolated rat hearts (n = 8-15 per experiment) subjected to regional ischaemia and treated with various free radical scavengers and spin trap agents. Reoxygenation automaticity was similarly studied in isolated guinea pig papillary muscles (n = 6-13 per experiment). MEASUREMENTS and RESULTS - In isolated rat hearts early reperfusion ventricular arrhythmias were unaltered by superoxide dismutase (1 X 10(5) IU.litre-1), catalase (1 X 10(6) IU.litre-1), N-tert-butyl-alpha-phenylnitrone (30 mumols.litre-1), 5,5-dimethyl-1-pyrroline-N-oxide (1 mmol.litre-1), or the combination of superoxide dismutase 1 X 10(5) IU.litre-1, catalase 1 X 10(6) IU.litre-1, and mannitol 10 mol.litre-1, or by the generation of the free radical .OH (Fe:ADP plus dihydroxyfumerate). In the isolated reoxygenated guinea pig papillary muscle, the incidence of reoxygenation automaticity was significantly reduced by verapamil 5 mumols.litre-1 but not by the following free oxygen radical scavengers: reduced glutathione (0.5 mmol.litre-1), N-acetyl cysteine (1 mmol.litre-1), the combination of superoxide dismutase (3 X 10(4) IU.litre-1) and catalase (5 X 10(3) IU.litre-1), or by pretreatment with allopurinol (30 mg.kg-1). Generating systems of .O2- or .OH induced relatively slow electrophysiological changes, including a decreased action potential duration. Reperfusion ventricular fibrillation in the rat heart was increased by increasing the extracellular calcium concentration from 1.25 to 1.9 or 2.5 mmol.litre-1, or by prolongation of the ischaemic time. CONCLUSIONS - Because of (a) the lack of an arrhythmogenic effect of free radical generating systems or of scavengers of free radicals, (b) the calcium sensitivity of reperfusion arrhythmias, and (c) the relatively slow time course of electrophysiological changes induced by free radical generating systems, we propose that free radicals are unlikely to be the prime cause of early ventricular arrhythmias in the systems that we tested. The mechanism of such arrhythmias is more likely to be a calcium sensitive process. The relatively slow electrophysiological changes mediated by free radicals suggest that these agents can cause delayed membrane change.
authors.affiliation: Medical Research Council Ischaemic Heart Disease Research Unit, University of Cape Town, Medical School, Observatory, Cape Town, South Africa.
authors.forename: W A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: P
authors.initials: P
authors.lastname: Owen
authors.forename: S C
authors.initials: SC
authors.lastname: Dennis
authors.forename: S
authors.initials: S
authors.lastname: Saman
authors.forename: L H
authors.initials: LH
authors.lastname: Opie
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002118:Calcium / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D010100:Oxygen; D051381:Rats; D013482:Superoxide Dismutase / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D005609:Free Radicals; D006861:Hydrogen Peroxide; D014700:Verapamil; D002374:Catalase; D013482:Superoxide Dismutase; D004110:Diltiazem; D010100:Oxygen; D002118:Calcium