Interaction of edrophonium with muscarinic acetylcholine M-2 and M-3 receptors

Background: It has been reported that edrophonium can antagonize the negati ve chronotropic effect of carbachol. This study was undertaken to evaluate in detail the interaction of edrophonium with muscarinic M-2 and M-3 recept ors. Methods: A functional study was conducted to evaluate the effects of edroph onium on the concentration-response curves for the negative chronotropic ef fect and the bronchoconstricting effect of carbachol in spontaneously beati ng right atria and tracheas of guinea pigs. An electrophysiologic study was conducted to compare the effects of edrophonium on carbachol-, guanosine t riphosphate (GTP)gamma S-, and adenosine-induced outward K+ currents in gui nea Dig atrial cells by whole cell voltage clamp technique. A radioligand b inding study was conducted to examine the effects of edrophonium on specifi c [H-3]N-methylscopolamine (NMS) binding to guinea pig atrial (M-2) and sub mandibular gland (M-3) membrane preparations, and on atropine-induced disso ciation of [H-3]NMS. Results: Edrophonium shifted rightward the concentration-response curves fo r the negative chronotropic and bronchoconstricting effects of carbachol in a competitive manner. The pA(2) values for cardiac and tracheal muscarinic receptors were 4.61 and 4.03, respectively. Edrophonium abolished the carb achol-induced outward current without affecting the GTP gamma S- and adenos ine-induced currents in the atrial cells. Edrophonium inhibited [H-3]NMS bi nding to M-2 and M-3 receptors in a concentration-dependent manner. The pse udo-Hill coefficient values and apparent dissociation constants of edrophon ium for M-2 and M-3 receptors were 1.02 and 1.07 and 21 and 34 muM, respect ively. Edrophonium also changed dissociation constant values of [H-3]NMS wi thout affecting its maximum binding capacities. Conclusion: Edrophonium binds to muscarinic M-2 and M-3 receptors nonselect ively, and acts as a competitive antagonist.