Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury

Giuseppe M. Campo, Francesco Squadrito, Salvatore Campo, Domenica Altavilla, Cristina Quartarone, Stefano Ceccarelli, Marcella Ferlito, Angela Avenoso, Giovanni Squadrito, Antonino Saitta, Achille P. Caputi

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1493-1503
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume30
Issue number8
DOIs
StatePublished - Aug 1998

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Keywords

  • Antioxidant
  • Free radicals
  • Lipid peroxidation
  • Myocardial ischemia/reperfusion injury
  • Raxofelast
  • Vitamin E

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Campo, G. M., Squadrito, F., Campo, S., Altavilla, D., Quartarone, C., Ceccarelli, S., Ferlito, M., Avenoso, A., Squadrito, G., Saitta, A., & Caputi, A. P. (1998). Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury. Journal of Molecular and Cellular Cardiology, 30(8), 1493-1503. https://doi.org/10.1006/jmcc.1998.0713