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Xanthine oxidase contributes to mitochondrial ROS generation in an experimental model of cocaine-induced diastolic dysfunction.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 2012 Dec; Vol. 60 (6), pp. 538-43. - Publication Year :
- 2012
-
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.
- Subjects :
- Adenosine Triphosphate metabolism
Allopurinol pharmacology
Animals
Antioxidants pharmacology
Diastole
Disease Models, Animal
Electron Transport Complex I metabolism
Electron Transport Complex III metabolism
Energy Metabolism
Enzyme Inhibitors pharmacology
Hemodynamics
Male
Mitochondria, Heart drug effects
Rats
Rats, Wistar
Superoxides metabolism
Ventricular Dysfunction, Left chemically induced
Ventricular Dysfunction, Left drug therapy
Ventricular Dysfunction, Left enzymology
Ventricular Dysfunction, Left physiopathology
Xanthine Oxidase antagonists & inhibitors
Cocaine
Mitochondria, Heart enzymology
Oxidative Stress drug effects
Reactive Oxygen Species metabolism
Ventricular Function, Left drug effects
Xanthine Oxidase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4023
- Volume :
- 60
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22967988
- Full Text :
- https://doi.org/10.1097/FJC.0b013e318271223c