Doxorubicin and local hyperthermia in the microcirculation of skeletal muscle

Doxorubicin HCl (Doxo) is an established intercalating antitumor drug. Specific side effects of Doxo primarily affect the cardiac muscle tissue to cause cardiac arrhythmias and chronic cardiomyopathies. The mechanism of action of these side effects is incompletely understood. Thus, the first objective of the present study was to test whether Doxo might have a direct effect on the microcirculation of muscular tissue. We studied large and small arterioles and large venules in the cremaster muscle of rats before and after sequential infusion of 1 (low-dose) and 10 mg/kg (high-dose) Doxo. Large arterioles showed some constriction after low Doxo doses and pronounced constriction after high Doxo doses, whereas small arterioles showed a variable response to low Doxo doses. At high Doxo doses, small arterioles dilated almost maximally (80% of the maximal response to nitroprusside). The heart rate and the diameter of large venules did not change at high Doxo doses, although the blood pressure decreased. This indicates that Doxo directly affects skeletal muscle arterioles. The second purpose of this study was to determine whether local hyperthermia would influence the microcirculation of muscular tissue such that the systemic concentration of Doxo could be reduced. In this second series of experiments, we tested whether local hyperthermia would have an effect on the skeletal muscle microvasculature and whether Doxo would change that response. Local hyperthermia alone did not alter the diameter of small arterioles or large venules, but we observed constriction of large arterioles at temperatures above 37 degrees C and during continued (60-min) hyperthermia at 40 degrees C. The low dose of Doxo did not alter these microvascular diameters at 40 degrees C. However, local hyperthermia at 40 degrees C changed the response of small arterioles to low doxo doses (no vasodilation was observed). Large arterioles continued to constrict in response to Doxo during hyperthermia. These data suggest that large arteriolar responses could be partly responsible for the toxic effect of Doxo on cardiac muscle and that local hyperthermia potentiates that response.