Molecular mechanism of doxorubicin-induced anticholinergic effect in guinea-pig atria.
The molecular mechanisms of anticholinergic actions of doxorubicin were examined by electrophysiological methods in atria and myocytes isolated from guinea-pig heart. A direct anticholinergic action of doxorubicin was confirmed with antagonistic action on carbachol-induced negative inotropic effect in atria. Both carbachol and adenosine produced shortening of action potential duration in atria measured by a microelectrode method. Doxorubicin (10-100 microM) inhibited the carbachol-induced action potential shortening in a concentration-dependent manner. However, doxorubicin did not antagonize the shortening elicited by adenosine. The whole-cell voltage clamp technique was performed to induce the muscarinic acetylcholine-receptor-operated K+ current (IK.ACh) in atrial myocytes loaded with GTP or GTPgammaS, a nonhydrolysable analogue of GTP. Doxorubicin (1-100 microM) suppressed carbachol-induced IK.ACh in a concentration-dependent manner (IC50 = 5.6 microM). In contrast, doxorubicin (10 and 100 microM) suppressed neither adenosine-induced IK.ACh nor GTPgammaS-induced IK.ACh. These results indicate that doxorubicin produces a direct anticholinergic effect through the muscarinic receptors in atrial myocytes.
Department of Veterinary Pharmacology, School of Veterinary Medicine and Animal Sciences, Kitasato University, Towada, Aomori, Japan. hara@vmas.kitasato-u.ac.jp
Y
Y
Hara
K
K
Temma
Z
Z
Sekiya
A
A
Chugun
H
H
Kondo
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016275:Atrial Function / Q000187:drug effects* / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology*; D003864:Depression, Chemical; D004317:Doxorubicin / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D018679:Cholinergic Agonists; D018680:Cholinergic Antagonists; D014665:Vasodilator Agents; D004317:Doxorubicin; D002217:Carbachol; D000241:Adenosine