Acute and subacute effects of doxorubicin on rate and force of contraction and enzyme activities in isolated rat heart

Abstract

Acute and subacute effects of doxorubicin (DOX) on Ca²⁺ in the SR and changes in adrenergic and cholinergic responses were examined on isolated Wistar rat atrial muscle preparations. Acute exposure with 100 µM DOX caused a decrease in heart rate, left atrial force and percentage of post-rest contraction (PRC). It reduced both positive chronotropic and inotropic effects including maximal response of isoproterenol. DOX also caused a right shift of the cumulative concentration response curve of acetylcholine. In subacute treatment, rats treated with DOX (2.5 mg/kg i.p. on days 1 and 7) caused a less increase in PRC compared with control group, and no changes in response of isoproterenol and acetylcholine were observed. The activites of myosin ATPase and actomyosin ATPase determined in subacute treatment did not differ between DOX and control groups, but DOX group showed a decrease in CK activity. These results lead to the conclusion that acute effect of DOX depresses rate and force of isolated rat atrial contraction predominantly by decreasing the amount of Ca²⁺ in the SR. DOX can compete with acetylcholine for muscarinic receptor, and inhibits common pathway of adrenergic system. Subacute effect of DOX causes a decrease of Ca²⁺ in the SR without modifying either adrenergic or cholinergic system. DOX suppresses the CK activity, but not myosin and actomyosin ATPase.