2002 Fiscal Year Final Research Report Summary
Role of Muscarinic K Channels in Parasympthetic Regulation of Heart Beat
| Project/Area Number |
12670715
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Osaka University (2002)
National Cardiovascular Center Research Institute (2000-2001) |
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Principal Investigator |
YAMADA Mitsuhiko Osaka University Graduate School of Medicine, Department of Pharmacology II, Associate Professor, 医学系研究科, 助教授 (10263237)
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| Project Period (FY) |
2000 – 2002
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| Keywords | Parasympathetic nerve / Heart / Sinoatrial node / Negative chronotropic effect / Muscarinic receptor / Tertiapin / Muscarinic K channel / Adenylate Cyclase |
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| Research Abstract |
I found that honey bee toxin, tertiapin selectively blocks muscarinic K+ (KACh) channels in cardiac myocytes. Thus, I analyzed how tertiapin modulates the negative chronotropic effect of carbachol in isolated rabbit hearts perfused with Langendorff apparatus. In the presence of propranolol (100 nM), carbachol (1 nM - 10 μM) induced sinus bradycardia in a concentration-dependent manner. Tertiapin (300 nM) partially inhibited the effect of carbachol. The tertiapin-sensitive and -insensitive components were respectively induced by * 100 nM and > 1 nM carbachol in a concentration-dependent manner, and accounted for 〜75 and 〜25 % of the effect of 10 μM carbachol. Because the baroreflex is mediated by KACh channels, the present data indicate that the parasympathetic nerve termini secrete a relatively large quantity of acetylcholine in the baroreflex. The tertiapin-insensitive component seemed to arise from inhibition of a hyperpolarization-activated nonselective cation current caused by a decrease in a basal cAMP level by carbachol. In the presence of isoproterenol (100 nM), the tertiapin-sensitive and -insensitive components were respectively induced by * 10 nM and > 1 nM carbachol in a concentration-dependent manner, and both accounted for 〜50 % of the effect of 10 μM carbachol. Therefore, the contribution of inhibition of adenylate cyclase to the negative chronotropic effect of muscarinic receptor stimulation became larger, while that of KACh currents became smaller in the presence than absence of β-adrenergic stimulation. The fact that the tertiapin-sensitive component became more sensitive to carbachol in the presence than absence of isoproterenol indicates that β-adrenergic stimulation increases the sensitivity of either KACh channels to carbachol or sinoatrial action potential to KACh currents. Further studies are needed to discreminate these two possibilities.
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[Publications] Chachin, M., Fujita, A,, Matsuoka, T., Yamada, M., and Kurachi, Y.: "Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic b-cell-type KATP channels"J. Pharmacol. Exp. Ther.. 304. 1025-1032 (2003)
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