[The involvement of muscarinic M1 receptor in the regulation of action potentials in mouse isolated right atria].
We investigated the involvement of muscarinic M1 receptors in the regulation of action potentials, and its modulation by adrenergic signaling and its change by aging in mouse isolated right atria using a conventional glass microelectrode technique. In adult mice, acetylcholine (ACh) (3-10 microM) reduced the maximum upstroke velocity of action potential (Vmax) followed by an increase. In electrically driven atria, similar effects of ACh on Vmax were observed. McN-A-343 (100-300 microM), a M1 agonist, reduced Vmax, while M2 agonist oxotremorine (0.1-0.3 microM), increased it. Isoproterenol (3 nM), antagonized ACh- and McN-A-343-induced reduction of Vmax, and potentiated the ACh- and oxotremorine-induced increase. The effects of isoproterenol were mimicked by cholera toxin, a Gs-protein activator, and forskolin, a direct activator of adenylyl cyclase. H-89, a selective protein kinase-A inhibitor, abolished the antagonism by isoproterenol of ACh-induced reduction in Vmax. Calphostin C, a selective protein kinase-C inhibitor, but not pertussis toxin attenuated ACh-induced reduction in Vmax. These results show that 1) ACh-induced reduction of Vmax and its subsequent increase are mediated by the activation of muscarinic M1 and M2 receptors, respectively, 2) the M1 and M2 subtypes may exert a balancing action on each other, and 3) the beta-adrenergic activation antagonizes M1-mediated effects, and enhances M2-mediated effects, on Vmax. In young mice, ACh (5-10 microM) increased Vmax, which was abolished by AF-DX 116 (0.3 microM), a M2 antagonist. In aged mice, ACh did not affect Vmax up to a concentration of 10 microM. The present findings may be of importance in the occurrence of cardiac disfunction in aging.
Kimura
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Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
Nojima
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H
Islam
M A
MA
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology*; D000375:Aging / Q000502:physiology; D000818:Animals; D016275:Atrial Function; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000502:physiology*
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D009281:Naphthalenes; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D010095:Oxotremorine; D011493:Protein Kinase C; C058819:calphostin C; D007545:Isoproterenol; D000109:Acetylcholine