title: Oxidative capacities of cardiac and skeletal muscles of heart transplant recipients: mitochondrial effects of cyclosporin-A and its vehicle Cremophor-EL.
abstract: Chronic immunosuppressive treatment was suspected to alter maximal muscle oxidative capacity (Vmax ) of heart transplant recipients, leading to a limitation of their exercise tolerance. It remains undefined whether the mitochondrial respiratory chain (MRC) of right ventricle (RV) and vastus lateralis (VL) muscles were altered by immunosuppressants and/or their vehicles. Vmax was measured polarographically in saponin-skinned fibres of RV and VL biopsies of patients and compared with Vmax of healthy VL and myocardium. Effects of increasing concentrations (1-10-100 μM) of Sandimmune(®) , its vehicle, Cyclosporine (CsA) in ethanol (EtOH), or EtOH alone were tested. The vehicle's effects on MRC complexes were investigated using specific substrates and inhibitors. Ten months after grafting, Vmax of RV and VL of immunosuppressed patients were similar to their Vmax at time of transplantation and to that of control tissues. In Vitro, Sandimmune(®) significantly decreased Vmax while CsA in EtOH or EtOH exerted small and similar effects. Effects of the vehicle were higher than (RV) or identical to (VL) those of Sandimmune(®) . The sites of action of the vehicle on MRC were located on complexes I and IV. While unchanged under chronic immunosuppressive therapy, Vmax of RV and VL muscles was depressed by acute exposure to intravenous Sandimmune(®) in vitro, an effect attributed to its vehicle by inhibition of complexes I and IV of the MRC. This work provides an in vitro proof of a toxic effect on the mitochondria respiratory chain of the vehicle used in the intravenous formulation of Sandimmune(®) but with no clinical consequences in chronically immunosuppressed patients.
authors.affiliation: Service de Physiologie Clinique et des Explorations Fonctionnelles, équipe d'accueil EA3072 Hôpitaux Universitaires de Strasbourg, 67091, Strasbourg Cedex, France; Laboratoire de Physiologie, Pharmacologie et Phytothérapie, UFR SN, Université d'Abobo-Adjamé, 02 BP 801 Abidjan 02, Abidjan, Côte d'Ivoire; Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, PO Box KB 52, Korle Bu, Accra, Ghana.
authors.forename: Benoit Banga
authors.initials: BB
authors.lastname: N' Guessan
authors.forename: Hervé
authors.initials: H
authors.lastname: Sanchez
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Florence
authors.initials: F
authors.lastname: Ribera
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dufour
authors.forename: Eliane
authors.initials: E
authors.lastname: Lampert
authors.forename: Michel
authors.initials: M
authors.lastname: Kindo
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Bertrand
authors.initials: B
authors.lastname: Mettauer
mesh_terms: D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005260:Female; D005990:Glycerol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D019737:Transplants / Q000187:drug effects* / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D007166:Immunosuppressive Agents; D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D016572:Cyclosporine; D005990:Glycerol