DOXORUBICIN CARDIOMYOPATHY IS ASSOCIATED WITH A DECREASE IN CALCIUM RELEASE CHANNEL OF THE SARCOPLASMIC-RETICULUM IN A CHRONIC RABBIT MODEL

Doxorubicin is a highly effective cancer chemotherapeutic agent that p roduces a dose-dependent cardiomyopathy that limits its clinical usefu lness. Clinical and animal studies of morphological changes during the early stages of doxorubicin-induced cardiomyopathy have suggested tha t the sarcoplasmic reticulum, the intracellular membrane system respon sible for myoplasmic calcium regulation in adult mammalian heart, may be the early target of doxorubicin. To detect changes in the calcium p ump protein or the calcium release channel (ryanodine receptor) of the sarcoplasmic reticulum during chronic doxorubicin treatment, rabbits were treated with intravenous doxorubicin (1 mg/kg) twice weekly for 1 2 to 18 doses. Pair-fed controls received intravenous normal saline. T he severity of cardiomyopathy was scored by light and electron microsc opy of left ventricular papillary muscles. Developed tension was measu red in isolated atrial strips. In subcellular fractions from heart, [H -3]ryanodine binding was decreased in doxorubicin-treated rabbits (0.3 3+/-0.03 pmol/mg) compared with control rabbits (0.66+/-0.02 pmol/mg; P < 0.0001). The magnitude of the decrease in [H-3]ryanodine binding c orrelated with both the severity of the cardiomyopathy graded by patho logy score (light and electron microscopy) and the decrease in develop ed tension in isolated atrial strips. B(max) for [H-3]ryanodine bindin g and the amount of immunoreactive ryanodine receptor by Western blot analysis using sequence-specific antibody were both decreased, consist ent with a decrease in the amount of calcium release channel of sarcop lasmic reticulum in doxorubicin-treated rabbits. In contrast, there wa s no decrease in the amount or the activity of the calcium pump protei n of the sarcoplasmic reticulum in doxorubicin-treated rabbits. Doxoru bicin treatment did not decrease [H-3]ryanodine binding or the amount of immunoreactive calcium release channel of sarcoplasmic reticulum in skeletal muscle. Since the sarcoplasmic reticulum regulates muscle co ntraction by the cyclic uptake and release of a large internal calcium pool, altered function of the calcium release channel could lead to t he abnormalities of contraction and relaxation observed in the doxorub icin cardiomyopathy.