Oxidative capacities of cardiac and skeletal muscles of heart transplant recipients: mitochondrial effects of cyclosporin‐A and its vehicle Cremophor‐EL. (9th October 2012)

• Record Type: Journal Article
• Authors: N'Guessan, Benoit Banga; Sanchez, Hervé; Zoll, Joffrey; Ribera, Florence; Dufour, Stéphane; Lampert, Eliane; Kindo, Michel; Geny, Bernard; Ventura‐Clapier, Renée; Mettauer, Bertrand
• Is Part Of: Fundamental & clinical pharmacology. Volume 28:Number 2(2014)
• Page Start: 151
• Page End: 160
• Publication Date: 2012-10-09
• Subjects: Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/fcp.12002
• Languages: English
• ISSNs: 0767-3981

Abstract

<abstract abstract-type="main" id="fcp12002-abs-0001"> <title>Abstract</title> <p>Chronic immunosuppressive treatment was suspected to alter maximal muscle oxidative capacity (<italic>V</italic><sub>max</sub>) 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. <italic>V</italic><sub>max</sub> was measured polarographically in saponin‐skinned fibres of RV and VL biopsies of patients and compared with <italic>V</italic><sub>max</sub> of healthy VL and myocardium. Effects of increasing concentrations (1–10–100 μM) of Sandimmune<sup>®</sup>, 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, <italic>V</italic><sub>max</sub> of RV and VL of immunosuppressed patients were similar to their <italic>V</italic><sub>max</sub> at time of transplantation and to that of control tissues. In Vitro, Sandimmune<sup>®</sup> significantly decreased <italic>V</italic><sub>max</sub> 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<sup>®</sup>. The sites of action of the vehicle on MRC were located on complexes I and IV. While unchanged under chronic immunosuppressive therapy, <italic>V</italic><sub>max</sub> of RV and VL muscles was depressed by acute exposure to intravenous Sandimmune<sup>®</sup> 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<sup>®</sup> but with no clinical consequences in chronically immunosuppressed patients.</p> </abstract>