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Xanthine Oxidase Contributes to Mitochondrial ROS Generation in an Experimental Model of Cocaine-Induced Diastolic Dysfunction

Vergeade, Aurélia PhD*; Mulder, Paul PhD*; Vendeville, Cathy*; Ventura-Clapier, Renée PhD; Thuillez, Christian MD, PhD*; Monteil, Christelle PhD

Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0b013e318271223c
Original Article
Abstract

Abstract: Recent studies have shown that long-term cocaine use induces diastolic impairment and a myocardial oxidative stress. Recently, we have reported that cocaine-induced cardiac dysfunction may be due to a mitochondrial reactive oxygen species (ROS) overproduction, which occurs at the same time as xanthine oxidase (XO) activation. In this work, we hypothesized that XO activation contributes to mitochondrial ROS overproduction, which in turn contributes to diastolic dysfunction. To test this, we used a well-established in vivo model of cocaine-induced diastolic dysfunction. In this experimental model treated with or without allopurinol, an inhibitor of XO, we measured mitochondrial ROS production and function. Mitochondrial alterations were characterized by an increase in oxygen consumption through complexes I and III, a reduction in ATP production, and an increased ROS production specifically in isolated interfibrillar mitochondria. Allopurinol treatment prevented the rise in mitochondrial ROS levels and the decrease in ATP production. In the same way, allopurinol treatment improved ventricular relaxation with a decrease in Tau, an index of left ventricle relaxation and of end-diastolic pressure volume relation. These results confirmed the critical role of XO in the sequence of events leading to cocaine-induced cardiac dysfunction.

Author Information

*University of Rouen, INSERM, Rouen, France

University of Paris-Sud, Institut National de la sante et de la Recherche Medicale, Châtenay-Malabry, France

University of Rouen, Aliments, Bioprocede, Toxicologue, Environnements Equipe d'accueil, Rouen, France.

Reprints: Christelle Monteil, PhD, UFR de Médecine et de Pharmacie, EA 4651, 22 boulevard Gambetta, 76183 Rouen, France (e-mail: christelle.monteil@univ-rouen.fr).

The authors report no funding or conflicts of interest.

Received June 1, 2012

Accepted August 27, 2012

© 2012 Lippincott Williams & Wilkins, Inc.