title: Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart.
abstract: 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 microM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt(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 microM cytochrome c/min/mg in control hearts vs. 14+/-3 microM 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.
authors.affiliation: Department of Physiology (EA 2689), Faculty of Medicine, University Lille 2, IFR 114 (IMPRT), Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.forename: Riadh
authors.initials: R
authors.lastname: Baccouch
authors.forename: Thomas
authors.initials: T
authors.lastname: Modine
authors.forename: Sebastien
authors.initials: S
authors.lastname: Preau
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Zannis
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.forename: Steve
authors.initials: S
authors.lastname: Lancel
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D054715:Cardiotoxins / Q000633:toxicity*; D016572:Cyclosporine / Q000494:pharmacology; D004317:Doxorubicin / Q000633:toxicity*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005453:Fluorescence; D005470:Fluorometry; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D054715:Cardiotoxins; D004317:Doxorubicin; D016572:Cyclosporine; D003576:Electron Transport Complex IV