title: Acetylcholine-induced biphasic effect on the maximum upstroke velocity of action potential in mouse right atria: interaction with beta-adrenergic signaling cascade.
abstract: Several lines of evidence suggest the molecular and functional entity of muscarinic M1 receptors in mammalian heart. We have reported that acetylcholine (ACh) reduces the maximum upstroke velocity of action potential (Vmax) through activation of muscarinic M1 receptors, which is followed by a muscarinic M2 receptor-mediated increase. The present study sought to determine whether activation of beta-adrenergic receptors modulates the muscarinic M1 and M2 receptor-mediated effects on Vmax in isolated mouse right atria. Intracellular recordings of spontaneous action potential were done using the conventional glass microelectrode technique. Isoproterenol (3 nM) completely antagonized ACh (5 microM)-induced reduction in Vmax. The antagonism was accompanied by a subsequent increase in Vmax. Propranolol (0.3 microM) abolished the effects of isoproterenol on ACh-induced changes in Vmax. Isoproterenol antagonized McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride) (300 microM, a muscarinic M1 receptor agonist)-induced reduction in Vmax. Oxotremorine (0.03 microM), a muscarinic M2 receptor agonist, did not affect Vmax by itself, but significantly increased it in the presence of 3 nM isoproterenol. The effects of isoproterenol were mimicked by cholera toxin (100 nM, 1 hr), a Gs-protein activator, and forskolin (10 nM), a direct activator of adenylyl cyclase. H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide++ +, 1 microM), a selective protein kinase (PK)-A inhibitor, abolished the antagonism by isoproterenol of ACh-induced reduction in Vmax. The present results suggest that activation of the beta-adrenergic-Gs-adenylyl cyclase system antagonizes ACh-induced reduction (muscarinic M1-mediated) and potentiates the subsequent increase (muscarinic M2 receptor-mediated) in Vmax. The beta-adrenergic antagonism of ACh-induced reduction in Vmax may involve cross-talk between PK-A and PK-C signaling pathways.
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*; D037361:Adenylate Cyclase Toxin; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D000276:Adjuvants, Immunologic; D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D018721:Muscarinic Agonists; D009281:Naphthalenes; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D010095:Oxotremorine; D002772:Cholera Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C058819:calphostin C; D007545:Isoproterenol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000109:Acetylcholine