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 tissue v 9.53 ± 2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73 ± 1.86 ΔABS/ ml v 1.61 ± 0.45 ΔABS/ml); endogenous antioxidant wasting [cardiac VE = 23.5 ± 10.2 nmol/g tissue v 61.4 ± 13.4 nmol/g tissue, cardiac reduced glutatione (GSH) = 2.15 ± 1.23 μmol/g protein v 7.34 ± 0.92 μmol/g protein and cardiac superoxide dismutase (SOD) = 8.9 ± 4.1 U/mg protein v 17.5 ± 4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4 ± 5.8 mmHg v 85.3 ± 6.2 mmHg); heart rate (HR) (275 ± 35 beats/ min v 368 ± 34 beats/min) and left-ventricular derivative developed force (LV dP/dt(max)) (1050 ± 187 mmHg/s v 2520 ± 194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23 ± 2.1 U/g tissue v 0.92 ± 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 tissue; P < 0.001 and CD = 4.01 ± 2.21 ΔABS/ml; P < 0.001, following the highest dose), restored the endogenous antioxidants VE (52.8 ± 14.2 nmol/g tissue; P < 0.001, following the highest dose), SOD (14.2 ± 2.7 U/mg protein; P < 0.001, following the highest dose) and GSH (4.92 ± 1.33 μmol/g protein; P < 0.005, following the highest dose, improved hemodynamic parameters (MAP = 68.1 ± 5.3 mmHg; P < 0.05, HR = 317 ± 27 beats/min; P < 0.05, LV dP/dt(max) = 1427 ± 143 mmHg/s; P < 0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO = 5.1 ± 1.5 U/g tissue; P < 0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.