Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

Journal Article · Sat May 01 04:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.01.006· OSTI ID:21344932

Montaigne, David; Marechal, Xavier ^[1]; Baccouch, Riadh ^[2]; Modine, Thomas ^[3]; Preau, Sebastien ^[1]; Zannis, Konstantinos ^[3]; Marchetti, Philippe ^[4]; Lancel, Steve ^[1]; Neviere, Remi ^[1]

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1. Department of Physiology (EA 2689), Faculty of Medicine, University Lille 2, IFR 114 (IMPRT), Lille (France)
2. Department of Pharmacy CHRU Lille (France)
3. Department of Cardiovascular Surgery, University Hospital, Lille (France)
4. INSERM U 837 Faculty of Medicine, University Lille 2, Lille (France)

The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 muM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt{sub max} of 105 +- 8 mN/s in control hearts vs. 49 +- 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 +- 0.2 in control hearts vs. 2.2 +- 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 +- 1 muM cytochrome c/min/mg in control hearts vs. 14 +- 3 muM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.

• OSTI ID: 21344932
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 244; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALDEHYDES
ANIMALS
ANTI-INFECTIVE AGENTS
ANTIBIOTICS
ANTINEOPLASTIC DRUGS
BODY
CARBOHYDRATES
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
CYCLOSPORINE
DOXORUBICIN
DRUGS
ENZYMES
FIBERS
GLUCOSE
HEART
HEXOSES
IMMUNOSUPPRESSIVE DRUGS
INHIBITION
MAMMALS
MEMBRANES
METABOLISM
MITOCHONDRIA
MONOSACCHARIDES
ORGANIC COMPOUNDS
ORGANS
OXIDASES
OXIDOREDUCTASES
PEPTIDES
PERFORMANCE
PERMEABILITY
PHYSICAL PROPERTIES
PROTEINS
RATS
RESPIRATION
RODENTS
SACCHARIDES
TIME DEPENDENCE
TOXICITY
VERTEBRATES