NADPH oxidase inhibition prevents cocaine-induced up-regulation of xanthine oxidoreductase and cardiac dysfunction.
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.
Isabelle
Marc
M
INSERM U644, UFR de Médecine et de Pharmacie, University of Rouen, 22 boulevard Gambetta, F-76183 Rouen, France.
Vergeade
Aurélia
A
Moritz
Fabienne
F
Dautréaux
Brigitte
B
Henry
Jean-Paul
JP
Lallemand
Françoise
F
Richard
Vincent
V
Mulder
Paul
P
Thuillez
Christian
C
Monteil
Christelle
C
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*
D000098:Acetophenones; D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D000493:Allopurinol; C056165:acetovanillone; D014968:Xanthine Dehydrogenase; D019255:NADPH Oxidases; D003042:Cocaine