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 µM) 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 (I K.ACh ) in atrial myocytes loaded with GTP or GTPgammaS, a nonhydrolysable analogue of GTP. Doxorubicin (1-100 µM) suppressed carbachol-induced I K.ACh in a concentration-dependent manner (IC 50 = 5.6 µM). In contrast, doxorubicin (10 and 100 µM) suppressed neither adenosine-induced I K.ACh nor GTPgammaS-induced I K.ACh . These results indicate that doxorubicin produces a direct anticholinergic effect through the muscarinic receptors in atrial myocytes.