PROTECTIVE EFFECT OF S12340 ON CARDIAC-CELLS EXPOSED TO OXIDATIVE STRESS

Oxidative stress induced by reactive oxygen species is one aspect of t he deleterious mechanisms involved in myocardial post-ischemic reperfu sion injury. The antioxidant properties of the new molecule S12340 hio }propyl]-1-oxa-2-oxo-3,8-diazaspiro[4.5]decane) were evaluated using t hree successive in vitro approaches mimicking the cardiac cell damages induced by reactive oxygen species released into the reperfused myoca rdium. (i) The effects of S12340 on lipid peroxidation were evaluated using an original cell-free model of non-enzymatic peroxidation of 1.3 2 mM arachidonic acid induced by reactive oxygen species generated pho tochemically. S12340 (13.2 mu M) inhibited by 29% the rate of oxidativ e fragmentation of monohydroperoxidized arachidonic acid into aldehydi c products. (ii) S12340 (10 mu M) inhibited by 96% and 58% the oxidati ve necrosis of cultured rat cardiomyocytes induced by xanthine oxidase (20 mU/ml) and monohydroperoxidized arachidonic acid (30 mu M), respe ctively. (iii) Superfusion of guinea-pig papillary muscle with monohyd roperoxidized arachidonic acid (20 mu M) resulted in marked alteration s of their electrophysiological and mechanical activities. These modif ications, maximal 15-17 min after the addition of lipid hydroperoxide, were completely abolished by S12340 (30 mu M).