ABNORMAL MYOCARDIAL CALCIUM HANDLING IN THE EARLY-STAGE OF ADRIAMYCINCARDIOMYOPATHY

Metabolic changes have been shown to precede mechanical abnormalities in the early stages of adriamycin cardiotoxicity. This study examines the early changes in calcium homeostasis and their mechanical implicat ions in a model of adriamycin cardiomyopathy. Hearts isolated from con trol and adriamycin-treated mts were coronary-perfused and isovolumic left ventricular (LV) pressure, coronary perfusion pressure and calciu m transients from aequorin-loaded cardiomyocytes were recorded. Treate d rats received three injections of adriamycin (6 mg/kg) for a period of 1 week. They were sacrificed for experiments 1-2 or 4-5 weeks after the final injection. The LV systolic and end-diastolic pressures were similar in both groups at varied external calcium concentrations (0.5 -2.0 mM). However, systolic levels of myoplasmic calcium were substant ially higher in the adriamycin-treated hearts, the difference being le ss at higher external calcium concentrations. Similar responses in bot h groups to paired pulse stimulation, increased stimulation frequency and caffeine (0.5-2.0 mM) were observed. However, adriamycin-treated h earts exhibited a smaller rise in LV developed pressure, as well as in systolic and diastolic calcium levels, in response to elevated corona ry perfusion pressure. The elevated intracellular systolic calcium lev el is suggestive of an early but persistent effect of adriamycin on th e calcium release channels of the the sarcoplasmic reticulum. That the elevated systolic myoplasmic calcium levels are not accompanied by an increase in inotropy suggests a decrease in myofibrillar calcium sens itivity in this model of the early stage of adriamycin cardiomyopathy.