Doxorubicin Affects the Cardiac Muscarinic System in the Rat

Journal of Veterinary Medical Science

Suzanne V. KLIMBERG⁴  Tai AKERA⁵  Takushi SASAKI¹  Akihito CHUGUN³  Richard H. KENNEDY²  Tsuyoshi UCHIDE¹  Yukio HARA³  Kyosuke TEMMA¹ 

[1]Department of Toxicology, School of Veterinary Medicine and Animal Sciences, Kitasato University

[2]Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences

[3]Department of Veterinary Pharmacology, School of Veterinary Medicine and Animal Sciences, Kitasato University

[4]Department of Surgery, University of Arkansas for Medical Sciences

[5]Merck Sharp and Dohm Research Laboratories Japan

关键词: adenosine receptor;    cardiotoxicity;    doxorubicin;    muscarinic receptor;    rat heart;   

DOI  :  10.1292/jvms.63.1315

学科分类：兽医学

来源: Japanese Society of Veterinary Science

【 摘 要 】

References(33)Cited-By(6)During the study on the mechanism of doxorubicin-induced cardiotoxicity, we observed that a long incubation (4 hr) with doxorubicin reduced the maximal negative inotropic effects of a muscarinic receptor agonist, carbachol. The mechanism responsible for this doxorubicin-induced reduction of the efficacy of carbachol was examined in isolated guinea pig hearts. In isolated left atrial muscle preparations, 1 hr incubation with 100 μM doxorubicin caused a parallel right-ward shift of the concentration-response curves for carbachol, but a longer (4 hr) incubation with this agent (30, 100 or 200 μM), caused a significant reduction of the magnitude of the negative inotropic effect of carbachol in addition to the concentration-dependent parallel right-ward shift. The 4-hr incubation with these concentrations of doxorubicin also reduced the maximal negative inotropic effect of an adenosine A1 receptor agonist, R-phenylisopropyl adenosine (R-PIA), without affecting the potency of this agonist. Doxorubicin (1 to 100 μM) reduced [3H]quinuclidinyl benzilate (QNB) binding in a concentration dependent manner, but failed to alter [3H]R-PIA binding. The decrease in the magnitude of the maximal negative inotropic effect by doxorubicin was caused by changes in the muscarinic system at steps common to the transduction of muscarinic and adenosine A1 receptor mechanisms.

【 授权许可】

Unknown