Acute presynaptic inhibition by doxorubicin of negative chrono- and inotropic responses to parasympathetic nerve stimulation in isolated, blood-perfused dog atrium.

Abstract

The clinical use of doxorubicin, an anthracycline antineoplastic agent, is limited by its cardiotoxicity. Although several previous reports have shown neurotoxic effects of doxorubicin, there is little information about the acute effects of doxorubicin on the autonomic nerve functions in the heart. Accordingly, to evaluate the effects of doxorubicin on the cardiac responses to autonomic nerve activation, we studied the effects of doxorubicin on the negative chrono- and inotropic responses to intracardiac parasympathetic nerve stimulation and acetylcholine (ACh), and the positive chrono- and inotropic responses to norepinephrine (NE) in the isolated, blood-perfused dog atrium. Doxorubicin (0.01-3 mumol), injected into the sinus node artery of the isolated atrium, induced negative inotropic effects dose dependently and weak negative chronotropic effects. Doxorubicin inhibited the negative chrono- and inotropic responses to parasympathetic nerve stimulation dose dependently. However, doxorubicin affected neither the negative chrono- and inotropic responses to ACh nor the positive chrono- and inotropic responses to NE. These results indicate that doxorubicin interacts with neither muscarinic receptors nor beta-adrenoceptors and suggest that doxorubicin inhibits the negative cardiac responses to parasympathetic nerve activation due to the inhibition of ACh release from nerve varicosities in the heart.