Effect of cyclosporin A and its vehicle on cardiac and skeletal muscle mitochondria: relationship to efficacy of the respiratory chain

1. Although cyclosporin (CsA) is considered to be the best immunosuppressiv e molecule in transplantation; it has been suspected to alter mitochondrial respiration of various tissues. 2 We evaluated the acute effect of CsA and its vehicle on maximal oxidative capacity (V-max) of cardiac, soleus and gastrocnemius muscles of rats by a n oxygraphic method in saponin skinned muscle fibres. The effects of Sandim mun (a formulation of CsA), vehicle of Sandimmun (cremophor and ethanol (Et OH)), CsA in EtOH and EtOH alone were tested. Increasing concentrations (5- 20-50-100 muM) of CsA (or vehicles) were used. 3 Sandimmun profoundly altered the V-max of all muscles. For example, at 20 muM, inhibition reached 18 +/-3, 23 +/-5, 45 +/-5%, for heart, soleus and gastrocnemius respectively. There were only minor effects of CsA diluted in EtOH and EtOH alone on V-max of cardiac muscle. Because the effects of veh icle on V-max were similar or higher than those of Sandimmun, the inhibitio n of oxidative capacity could be entirely attributed to the vehicle for all muscles. 4 Next, we investigated the potential sites of action of the vehicle on the different complexes of the mitochondrial respiratory chain by using specif ic substrates and inhibitors. The vehicle affected mitochondrial respiratio n mainly at the level of complex I (approximate to -85% in skeletal muscles , and -32% in heart), but also at complex IV (approximate to -26% for all m uscles). 5 The mechanism of action of the vehicle on the mitochondrial membrane and the implications for the clinical use of immunosuppressive drugs are discus sed.