title: Muscarinic M1 receptor activation reduces maximum upstroke velocity of action potential in mouse right atria.
abstract: We investigated whether acetylcholine affects cardiac action potentials through the muscarinic M1 in addition to M2 receptors in spontaneously beating mouse isolated right atria. A conventional glass microelectrode technique was used for the purpose. Acetylcholine (3-10 microM) reduced the maximum upstroke velocity of the action potentials (Vmax), followed by an increase. It shortened action potential duration at 90% repolarization, hyperpolarized the resting membrane and decreased the rate of beating. Atropine (3-100 nM) concentration dependently antagonized these effects of acetylcholine. Pirenzepine (10 and 30 nM), a selective muscarinic M1 receptor antagonist, antagonized acetylcholine (5 microM)-induced reduction of Vmax without affecting other effects of acetylcholine. In addition, pirenzepine (30 nM) induced an immediate and linear acceleration of the VmaX reduced by acetylcholine. In contrast, AF-DX 116 (11(¿2-[(diethylamino)-methyl]-1-piperidyl¿acetyl)-5,11-dihydro-6 H-pyridol[2,3-b][1,4]benzodiazepine-6-one base, 30-300 nM), a selective muscarinic M2 receptor antagonist, failed to antagonize acetylcholine-induced reduction of Vmax, but abolished its increase. It antagonized the shortening of action potential duration, membrane hyperpolarization and decreased the beating rate. McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride, 100 and 300 microM), a muscarinic M1 receptor agonist, reduced Vmax and prolonged action potential duration, while oxotremorine (100-300 nM), a muscarinic M2 receptor agonist, evoked reverse effects. These results suggest that acetylcholine exerts a mixed effect on Vmax, consisting of a reduction and a facilitation, possibly mediated by concurrent activation of muscarinic M1 and M2 receptors, respectively, in isolated right atria of mice.
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
authors.forename: M A
authors.initials: MA
authors.lastname: Islam
authors.forename: H
authors.initials: H
authors.lastname: Nojima
authors.forename: I
authors.initials: I
authors.lastname: Kimura
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008839:Microelectrodes; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010095:Oxotremorine / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects*
chemical_list: D018721:Muscarinic Agonists; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D010095:Oxotremorine; D000109:Acetylcholine; C048593:otenzepad