TY - JOUR
T1 - Oxidative capacities of cardiac and skeletal muscles of heart transplant recipients
T2 - Mitochondrial effects of cyclosporin-A and its vehicle Cremophor-EL
AU - N'Guessan, Benoit Banga
AU - Sanchez, Hervé
AU - Zoll, Joffrey
AU - Ribera, Florence
AU - Dufour, Stéphane
AU - Lampert, Eliane
AU - Kindo, Michel
AU - Geny, Bernard
AU - Ventura-Clapier, Renée
AU - Mettauer, Bertrand
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Cyclosporin-A
KW - Membrane
KW - Mitochondrial respiration
KW - Respiratory chain
KW - Skinned fibres
KW - Vehicle
UR - http://www.scopus.com/inward/record.url?scp=84895547580&partnerID=8YFLogxK
U2 - 10.1111/fcp.12002
DO - 10.1111/fcp.12002
M3 - Article
C2 - 23046032
AN - SCOPUS:84895547580
SN - 0767-3981
VL - 28
SP - 151
EP - 160
JO - Fundamental and Clinical Pharmacology
JF - Fundamental and Clinical Pharmacology
IS - 2
ER -