EFFECTS OF ADRIAMYCIN ON HEART MITOCHONDRIAL-FUNCTION IN RESTED AND EXERCISED RATS

The effect of Adriamycin(R) (ADM) administration on heart mitochondria was investigated in rats at rest and after an acute bout of maximal e xercise. ADM was given intravenously at a dosage of 8 mg/kg body weigh t 24 and 1 hr before rats were decapitated. Respiratory functions of t he isolated heart mitochondria were measured polarographically with bo t site 1 (pyruvate-malate and 2-oxoglutarate) and site 2 (succinate) s ubstrates. State 4 (basal) respiration was increased using all substra tes in ADM-treated rat hearts compared with non-drug control hearts. T he mitochondrial respiratory control index was decreased with ADM, but the reduction was due to an increase in state 4 rather than a decreas e of state 3 (ADP-stimulated) respiration. ADM administration abolishe d an exercise-induced elevation of state 3 respiration using all subst rates. There was no significant myocardial oxidative damage of dysfunc tion as evaluated by lipid peroxidation and antioxidant enzyme activit y. Addition of exogenous free radicals to the respiratory medium using hypoxanthine and xanthine oxidase resulted in significant deteriorati on of mitochondrial function in all parameters measured, but no drug- or exercise-specific patterns of damage were revealed. It is concluded that the current dose of ADM (20% of the established cumulative toxic dose) administered within 24 hr can interfere with normal heart mitoc hondrial function both at rest and during heavy exercise, but does not elicit overwhelming oxidative damage to the myocardium.