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).