The long-term objectives of this research is to identify the primary functional changes occurring in the heart following long-term treatment with the anthracycline antineoplastic drug doxorubicin. We have previously shown that doxorubicin cardiomyopathy in the rat be associated with characteristic baseline ECG, transmembrane potential, and contractile changes, and we have demonstrated that hearts from treated animals are less responsive to beta-adrenergic stimulation. We now propose to systematically relate these abnormalities to physiological and biochemical changes in cellular and subcellular systems using rats and rabbits. A key goal is to determine the role of calcium ion changes in doxorubicin cardiomyopathy, and we will test the specific hypothesis that this disease is associated with calcium deficiency in myocardial cells rather than overload, as is commonly believed. We will also attempt to identify (a) specific changes in cellular membrane systems that control intracellular calcium (sarcolemma, sarcoplasmic reticulum) and (b) ionic changes responsible for observed ECG and transmembrane potential changes. Finally, we will assess the possible mechanisms underlying altered adrenergic responsiveness in this disease. This research will enhance understanding of a very important iatrogenic cardiomyopathy and provide useful information on heart failure mechanisms. Furthermore, the data from this research should be helpful in devising methods of preventing--or treating--anthracycline-induced cardiac muscle abnormalities. We will use the following methodologies: voltage clamping of single myocytes, indo-1 measurements of intracellular free Ca++, radiolabeled ligands, enzyme assays, and Ca++ uptake and binding methods.
| Keung, E C; Toll, L; Ellis, M et al. (1991) L-type cardiac calcium channels in doxorubicin cardiomyopathy in rats morphological, biochemical, and functional correlations. J Clin Invest 87:2108-13 |
| Toll, L (1990) Mu-opioid receptor binding in intact SH-SY5Y neuroblastoma cells. Eur J Pharmacol 176:213-7 |
| Jensen, R A (1986) Doxorubicin cardiotoxicity: contractile changes after long-term treatment in the rat. J Pharmacol Exp Ther 236:197-203 |
