Protective effect of S12340 on cardiac cells exposed to oxidative stress.
Oxidative stress induced by reactive oxygen species is one aspect of the deleterious mechanisms involved in myocardial post-ischemic reperfusion injury. The antioxidant properties of the new molecule S12340 (8-[3-(3,5-diterbutyl-4-hydroxyphenyl-thio)propyl]-1-oxa-2- oxo-3,8-diazaspiro[4.5]decane) were evaluated using three successive in vitro approaches mimicking the cardiac cell damages induced by reactive oxygen species released into the reperfused myocardium. (i) The effects of S12340 on lipid peroxidation were evaluated using an original cell-free model of non-enzymatic peroxidation of 1.32 mM arachidonic acid induced by reactive oxygen species generated photochemically. S12340 (13.2 microM) inhibited by 29% the rate of oxidative fragmentation of monohydroperoxidized arachidonic acid into aldehydic products. (ii) S12340 (10 microM) inhibited by 96% and 58% the oxidative necrosis of cultured rat cardiomyocytes induced by xanthine oxidase (20 mU/ml) and monohydroperoxidized arachidonic acid (30 microM), respectively. (iii) Superfusion of guinea-pig papillary muscle with monohydroperoxidized arachidonic acid (20 microM) resulted in marked alterations of their electrophysiological and mechanical activities. These modifications, maximal 15-17 min after the addition of lipid hydroperoxide, were completely abolished by S12340 (30 microM).
Iliou
J P
JP
Division Pathologies Cardiaques et Vasculaires, Institut de Recherches Servier, Suresnes, France.
Thollon
C
C
Robin
F
F
Cambarrat
C
C
Guillonneau
C
C
Régnier
G
G
Lenaers
A
A
Vilaine
J P
JP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D002478:Cells, Cultured; D006168:Guinea Pigs; D007042:Hypoxanthines / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009336:Necrosis; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D011341:Probucol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013141:Spiro Compounds / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000378:metabolism
D000975:Antioxidants; D001095:Arachidonic Acids; D007042:Hypoxanthines; D013141:Spiro Compounds; C085571:S 12340; D014969:Xanthine Oxidase; D011341:Probucol