title: NADPH oxidase inhibition prevents cocaine-induced up-regulation of xanthine oxidoreductase and cardiac dysfunction.
abstract: Oxidative stress is involved in the pathogenesis of cocaine-induced cardiomyopathy. In the present study, we aimed to determine the enzymatic sources of reactive oxygen species (ROS) production, namely NADPH oxidase and xanthine oxidoreductase (XOR) in male Wistar rats treated for 7 days with cocaine (2x7.5 mg/kg/day, ip) or cocaine with a NADPH oxidase inhibitor (apocynin, 50 mg/kg/day, po) or a XOR inhibitor (allopurinol, 50 mg/kg/day, po). Cocaine-induced cardiac dysfunction is associated with an increase in NADPH oxidase and XOR activities (59% and 29%, respectively) and a decrease in catalase activity. Apocynin or allopurinol treatment prevents the cocaine-induced cardiac alteration by restoration of cardiac output, stroke volume and fractional shortening. This is associated with a reduction of the myocardial production of superoxide anions and an enhancement of catalase activity. Surprisingly, apocynin treatment prevents XOR up-regulation supporting the hypothesis that NADPH oxidase-derived ROS play a role in modulating ROS production by XOR. These data suggest that NADPH and xanthine oxidase act synergically to form myocardial ROS and clearly demonstrate that their inhibition may be critical in preventing the initiation and progression of cocaine-induced LV dysfunction.
authors.affiliation: INSERM U644, UFR de Médecine et de Pharmacie, University of Rouen, 22 boulevard Gambetta, F-76183 Rouen, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Isabelle
authors.forename: Aurélia
authors.initials: A
authors.lastname: Vergeade
authors.forename: Fabienne
authors.initials: F
authors.lastname: Moritz
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dautréaux
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.forename: Françoise
authors.initials: F
authors.lastname: Lallemand
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Christelle
authors.initials: C
authors.lastname: Monteil
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000493:Allopurinol / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D003042:Cocaine / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000201:enzymology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D014968:Xanthine Dehydrogenase / Q000096:biosynthesis*
chemical_list: D000098:Acetophenones; D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D000493:Allopurinol; C056165:acetovanillone; D014968:Xanthine Dehydrogenase; D019255:NADPH Oxidases; D003042:Cocaine