Acetylcholine-Induced Biphasic Effect on the Maximum Upstroke Velocity of Action Potential in Mouse Right Atria: Interaction With β-Adrenergic Signaling Cascade

The Japanese Journal of Pharmacology

Ikuko Kimura¹  Hiroshi Nojima¹  Md. Amirul Islam¹ 

[1] Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

关键词: Muscarinic M1 receptor;    β-Adrenergic-muscarinic interaction;    Vmax;    Action potential;    Right atrium;   

DOI  :  10.1254/jjp.78.181

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(28)Cited-By(1)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 β-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 μM)-induced reduction in Vmax. The antagonism was accompanied by a subsequent increase in Vmax. Propranolol (0.3 μM) abolished the effects of isoproterenol on ACh-induced changes in Vmax. Isoproterenol antagonized McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride) (300 μM, a muscarinic M1 receptor agonist)-induced reduction in Vmax. Oxotremorine (0.03 μM), 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 μM), 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 β-adrenergic-Gs-adenylyl cyclase system antagonizes ACh-induced reduction (muscarinic M1-mediated) and potentiates the subsequent increase (muscarinic M2 receptor-mediated) in Vmax. The β-adrenergic antagonism of ACh-induced reduction in Vmax may involve cross-talk between PK-A and PK-C signaling pathways.

【 授权许可】

Unknown