Immunosuppressive treatment affects cardiac and skeletal muscle mitochondria by the toxic effect of vehicle

order to examine whether immunosuppressive treatment could be responsible f or the reduced exercise capacity of heart transplant recipients (HTR), we s tudied the effects of long-term immunosuppressive treatment with cyclospori n A (CsA) and its vehicle (2/3 cremophor and 1/3 alcohol diluted in olive o il) on in situ mitochondrial respiration of different muscles. Rats were fe d for 3 weeks with 10 or 25 mg/kg/day CsA in its vehicle (CsA10 and CsA25 g roups), or vehicle or H2O. Oxygen consumption rate was measured in saponin skinned fibers without (V-0) and with ADP until maximal respiration (V-max) was reached and K-M for ADP as well as V-max were calculated using non-lin ear fit of the Michaelis-Menten equation. In the cardiac muscle of the CsA2 5 group, V-0 and V-max were decreased by immunosuppressive treatment respec tively from 6.33 +/- 0.51 to 3.18 +/- 0.3 mu mol O-2/min/g dw (P<0.001) and from 29.0 +/- 1.5 to 18.1 +/- 1.6 mu mol O-2/min/g dw (P<0.001), an effect which could be entirely attributed to the vehicle itself, with no differen ce between CsA10 and CsA25. Regulation of cardiac mitochondrial respiration by ADP was altered by vehicle with the K-M for ADP decreasing from 371 +/- 37 to 180 +/- 21 M (P<0.001). A similar trend was observed in the diaphrag m or soleus, although to a lesser extent. In contrast, V-0 and V-max decrea sed in glycolytic gastrocnemius muscle respectively from 1.7 +/- 0.2 to 0.9 4 +/- 4.14 (P<0.01) and from 6.8 +/- 0.3 to 5.1 +/- 0.4 mu mol O-2/min/g dw (P<0.001) in the CsA25 group, but the main effects could be attributed to CsA itself. It was concluded that immunosuppressive treatment induces a del eterious effect on cardiac and skeletal muscle oxidative capacities, mainly due to cremophor, the main component of vehicle. O 2000 Academic Press.