Abstract
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.
