Interaction of class III antiarrhythmic drugs with muscarinic M2 and M3 receptors: radioligand binding and functional studies.

We have recently reported that class III antiarrhythmic drugs inhibit the muscarinic acetylcholine (ACh) receptor-operated K+ current (IK,ACh) in guinea-pig atrial cells by different molecular mechanisms. The data obtained from the patch-clamp study suggest that D,L-sotalol inhibits IK,ACh by blocking the muscarinic receptors, whereas MS-551 inhibits the K+ current by blocking the muscarinic receptors and depressing the function of the K+ channel itself and/or the guanine nucleotide-binding protein (G protein). This study was undertaken to determine whether the class III antiarrhythmic drugs D,L-sotalol and MS-551 interact with the muscarinic receptors of cardiac and peripheral tissues. Both drugs inhibited concentration dependently the specific [3H]N-methylscopolamine ([3H]-NMS) binding to membrane preparations obtained from guinea-pig atria and submandibular glands. The competition curves of these drugs for [3H]-NMS binding to glandular membranes were monophasic, suggesting competition with [3H]-NMS at a single site. Although the competition curve of D,L-sotalol for [3H]-NMS binding to atrial membranes was monophasic, that of MS-551 was biphasic and showed high- and low-affinity states of binding. D,L-Sotalol showed slightly, but significantly, higher affinity for cardiac-type muscarinic receptors (M2) than for glandular-type muscarinic receptors (M3). The inhibition constant (Ki) for MS-551 in glandular membranes was also slightly greater than the high-affinity Ki value for the drug in atrial membranes. In guinea-pig left atria and ilea, D,L-sotalol shifted the concentration-response curves for the negative inotropic effect and the contracting effect of carbachol in a parallel manner. The slopes of Schild plot were not significantly different from unity, suggesting competitive antagonism, and the pA2 for D,L-sotalol in left atria was slightly greater than that in ilea. MS-551 also shifted the concentration response curve for the negative inotropic effect of carbachol in atrial preparations to a greater extent than that for the contracting effect in ileal preparations, although MS-551 failed to show a pure competitive antagonism. These results suggest that both D,L-sotalol and MS-551 interact with cardiac M2 and peripheral M3 receptors, and that at high concentrations they exert anticholinergic activity in cardiac and peripheral tissues.