抄録
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 μM) 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 μM), a M1 agonist, reduced Vmax, while M2 agonist oxotremorine (0.1-0.3 μM), 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 β-adrenergic activation antagonizes M1-mediated effects, and enhances M2-mediated effects, on Vmax. In young mice, ACh (5-10 μM) increased Vmax, which was abolished by AF-DX 116 (0.3 μM), a M2 antagonist. In aged mice, ACh did not affect Vmax up to a concentration of 10 μM. The present findings may be of importance in the occurrence of cardiac disfunction in aging.
