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 Ih 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 Delta ABS/ ml v 1.61 +/- 0.45 Delta ABS/ml); endogenous antioxidant wasting [cardiac VE = 23.5 +/- 10.2 nmol/g tissue v 61.4 +/- 13.4 nmol/g tissue, cardiac reduced grutatione (GSH) = 2.15 +/- 1.23 mu mol/g protein v 7.34 +/- 0.92 mu mol/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/df(max)) (1050 +/- 187 mmHg/s v 2520 +/- 194 mmHg/s); and cardiac neutrophir 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 Delta ABS/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 mu mol/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. (C) 1998 Academic Press