Beneficial Effect of Raxofelast, an Hydrophilic Vitamin E Analogue, in the Rat Heart After Ischemia and Reperfusion Injury

Several studies report that among the antioxidant agents used to reduce injury after myocardial ischemia/reperfusion, analogues of vitamin E (VE) seem to have a significant efficacy. Raxofelast is a potent antioxidant agent under investigation, structurally related to VE, having an excellent bioavailability and favourable physicochemical properties. We assessed raxofelast in a rat model of myocardial damage induced by 1 h of left coronary artery occlusion followed by 6 h of reperfusion. Myocardial ischemia/reperfusion produced: wide tissue necrosis (50.3±10.3%); membrane peroxidation, evaluated by assessing cardiac malondialdehyde (MAL) (87.8±15.8 nmol/g tissuev9.53±2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73±1.86 ΔABS/mlv1.61±0.45 ΔABS/ml); endogenous antioxidant wasting [cardiac VE=23.5±10.2 nmol/g tissuev61.4±13.4 nmol/g tissue, cardiac reduced glutatione (GSH)=2.15±1.23μmol/g proteinv7.34±0.92μmol/g protein and cardiac superoxide dismutase (SOD)=8.9±4.1 U/mg proteinv17.5±4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4±5.8 mmHgv85.3±6.2 mmHg); heart rate (HR) (275±35 beats/minv368±34 beats/min) and left-ventricular derivative developed force (LV dP/dtmax) (1050±187 mmHg/sv2520±194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23±2.1 U/g tissuev0.92±0.12 U/g tissue). Administration of raxofelast (25, 50 and 100 mg/kg i.p. 5 min after occlusion) limited myocardial necrosis (22.3±14.8%P<0.005, following the highest dose), reduced lipid peroxidation (MAL=43.5±14.7 nmol/g tissueP<0.001 and CD=4.01±2.21 ΔABS/mlP<0.001, following the highest dose), restored the endogenous antioxidants VE (52.8±14.2 nmol/g tissueP<0.001, following the highest dose), SOD (14.2±2.7 U/mg proteinP<0.001, following the highest dose) and GSH (4.92±1.33μmol/g proteinP<0.005, following the highest dose), improved hemodynamic parameters (MAP=68.1±5.3 mmHgP<0.05, HR=317±27 beats/minP<0.05, LV dP/dtmax=1427±143 mmHg/sP<0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO=5.1±1.5 U/g tissueP<0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.