title: Selectivity of class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide for peripheral muscarinic M2 and M3 receptors.
abstract: The interactions of the class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide with peripheral muscarinic receptors were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All the agents inhibited the specific [3H]NMS binding to membrane preparations obtained from guinea pig submandibular gland (SG) and urinary bladder (UB) smooth muscle. The competition curves of these agents for [3H]NMS binding to SG membranes were monophasic, indicating competition with [3H]NMS at a single site. Comparison of results with those of our previous binding experiments using guinea pig left atrial (LA) membranes, showed that pirmenol had sevenfold lower affinity for glandular-type muscarinic receptors (M3) than for cardiac-type muscarinic receptors (M2). On the other hand, the dissociation constants (Ki) for disopyramide and pentisomide in SG were comparable to the high-affinity Ki values for these agents at M2 receptors. The competition curves of the three agents for [3H]NMS binding to UB membranes were biphasic and showed high- and low-affinity states of binding. The high- and low-affinity Ki values for pirmenol in UB were similar to its Ki values at M2 and M3 receptors obtained in LA and SG, respectively. The high-affinity Ki values for disopyramide and pentisomide were consistent with the respective Ki values determined in SG, whereas the low-affinity binding sites for these agents were presumably the result of their allosteric interactions with the receptors. All agents at higher concentrations slowed the dissociation of [3H]NMS elicited by an excess of atropine in both UB and SG, thus indicating allosteric interactions.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Endou
authors.forename: Y
authors.initials: Y
authors.lastname: Hattori
authors.forename: S
authors.initials: S
authors.lastname: Gando
authors.forename: M
authors.initials: M
authors.lastname: Kanno
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D004206:Disopyramide / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D019832:N-Methylscopolamine; D010880:Piperidines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism; D013363:Submandibular Gland / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011437:Propylamines; D011725:Pyridines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C045930:propisomide; D004206:Disopyramide; D019832:N-Methylscopolamine; C024318:pirmenol