ACUTE PRESYNAPTIC INHIBITION BY DOXORUBICIN OF NEGATIVE CHRONOTROPIC AND INOTROPIC RESPONSES TO PARASYMPATHETIC NERVE-STIMULATION IN ISOLATED, BLOOD-PERFUSED DOG ATRIUM

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 informat ion about the acute effects of doxorubicin on the autonomic nerve func tions in the heart. Accordingly, to evaluate the effects of doxorubici n on the cardiac responses to autonomic nerve activation, we studied t he effects of doxorubicin on the negative chrono- and inotropic respon ses to intracardiac parasympathetic nerve stimulation and acetylcholin e (ACh), and the positive chrono- and inotropic responses to norepinep hrine (NE) in the isolated, blood-perfused dog atrium. Doxorubicin (0. 01-3 mu mol), injected into the sinus node artery of the isolated atri um, induced negative inotropic effects dose dependently and weak negat ive chronotropic effects. Doxorubicin inhibited the negative chrono- a nd inotropic responses to parasympathetic nerve stimulation dose depen dently. However, doxorubicin affected neither the negative chrono- and inotropic responses to ACh nor the positive chrono- and inotropic res ponses to NE. These results indicate that doxorubicin interacts with n either muscarinic receptors nor P-adrenoceptors and suggest that doxor ubicin inhibits the negative cardiac responses to parasympathetic nerv e activation due to the inhibition of ACh release from nerve varicosit ies in the heart.