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

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Several lines of evidence suggest the molecular and functional entity of muscarinic M<SUB>1</SUB> receptors in mammalian heart. We have reported that acetylcholine (ACh) reduces the maximum upstroke velocity of action potential (V<SUB>max</SUB>) through activation of muscarinic M<SUB>1</SUB> receptors, which is followed by a muscarinic M<SUB>2</SUB> receptor-mediated increase. The present study sought to determine whether activation of β-adrenergic receptors modulates the muscarinic M<SUB>1</SUB> and M<SUB>2</SUB> receptor-mediated effects on V<SUB>max</SUB> 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 V<SUB>max</SUB>. The antagonism was accompanied by a subsequent increase in V<SUB>max</SUB>. Propranolol (0.3 μM) abolished the effects of isoproterenol on ACh-induced changes in V<SUB>max</SUB>. Isoproterenol antagonized McN-A-343 (4-(<I>m</I>-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride) (300 μM, a muscarinic M<SUB>1</SUB> receptor agonist)-induced reduction in V<SUB>max</SUB>. Oxotremorine (0.03 μM), a muscarinic M<SUB>2</SUB> receptor agonist, did not affect V<SUB>max</SUB> 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 G<SUB>s</SUB>-protein activator, and forskolin (10 nM), a direct activator of adenylyl cyclase. H-89 (<I>N</I>-[2-(<I>p</I>-bromocinnamylamino)ethyl]5-isoquinolinesulphonamide, 1 μM), a selective protein kinase (PK)-A inhibitor, abolished the antagonism by isoproterenol of ACh-induced reduction in V<SUB>max</SUB>. The present results suggest that activation of the β-adrenergic-G<SUB>s</SUB>-adenylyl cyclase system antagonizes ACh-induced reduction (muscarinic M<SUB>1</SUB>-mediated) and potentiates the subsequent increase (muscarinic M<SUB>2</SUB> receptor-mediated) in V<SUB>max</SUB>. The β-adrenergic antagonism of ACh-induced reduction in V<SUB>max</SUB> may involve cross-talk between PK-A and PK-C signaling pathways.

収録刊行物

  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 78(2), 181-190, 1998-10-01

    The Japanese Pharmacological Society

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各種コード

  • NII論文ID(NAID)
    10008680735
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    00215198
  • NDL 記事登録ID
    4591515
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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