2006 Fiscal Year Final Research Report Summary
Molecular pharmacological research for regulation and disorder of cardiac myocytes
| Project/Area Number |
16390064
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Yamagata University |
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Principal Investigator |
ENDOH Masao Yamagata University, Cardiovascular Pharmacology, Professor, 副学長 (40004668)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Kuniaki Yamagata University, Cardiovascular Pharmacology, Professor, 医学部, 教授 (10184459)
NISHIMARU Kazuhide Yamagata University, Cardiovascular Pharmacology, Assistant, 医学部, 助手 (60361250)
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| Project Period (FY) |
2004 – 2006
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| Keywords | mouse ventricular cardiomyocytes / dog ventricular cardiomyocytes / Ca^<2+> sensitizers / Ca^<2+> mobilizers / force-frequency relationship / endothelin / norepinephrine / Na^+ / Ca^<2+> exchanger |
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| Research Abstract |
The heart is able to maintain circulating blood volume required for wide range of adaptation of vital organs by an immediate increase in cardiac output by means of well-developed regulatory systems of cardiac contractility. Contractile regulation is achieved by cardiac intrinsic and/or external regulatory mechanisms, in both of which Ca^<2+> ions play a pivotal role. The regulation by Ca^<2+> is achieved by Ca^<2+> binding to troponin C (central mechanism), alteration of Ca^<2+> mobilization (upstream mechanism), and thin filament regulation of cross-bridge cycling and/or regulation of cross-bridge cycling itself (downstream mechanism). Regulation and disorder of cardiac excitation-contraction coupling occur at the level of selective or concomitant modulation of these Ca^<2+> regulatory processes. Experiments were carried out to elucidate the regulatory mechanisms of action of endothelin-1 (ET-1) that has been shown to be released in the systemic circulation of patients with various ca
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rdiovascular diseases including ischemic heart disease and congestive heart failure. Cell shortening and indo-1 fluorescent signals were detected simultaneously in mouse and dog single ventricular myocytes. In the dog, ET-1 induced a positive or negative inotropic effect by cross-talk with norepinephrine (NE) depending on the NE concentration. By contrast, in the mouse ventricular myocytes, ET-1 elicited a pronounced negative inotropic effect through the activation of Na^+/Ca^<2+> exchanger, which is susceptible to SEA 0400 and PKC inhibitors. Thus the inotropic response to ET-1 show a wide range of species-dependent variation. Since the mouse heart is employed as pathological models of mammalian heart diseases because of its ease for genetic manipulation, the difference in receptor-mediated regulation in this species from larger mammalian species has to be taken into consideration in analysis the etiology underlying the pathological outcome. The mechanism of action of a novel cardiotonic agent levosimendan was analyzed by means of aequorin-loaded dog ventricular myocardium. It was found that over a wide range of levosimendan concentration, it elicited a positive inotropic effect by combination of Ca^<2+> mobilization and myofilament Ca^<2+> sensitization. In the final stage of cardiovascular research of the main investigator before retirement the characteristics of crucial regulatory mechanisms, such as force-frequency relationship, PDE 3 inhibitors, and Ca^<2+> sensitizers are summarized in relation to their pathophysiological relevance, and the future direction of development of novel cardiovascular drugs. Less
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Research Products
(40 results)
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[Journal Article] Cross-talk between β_1-adrenoceptors and ET_A receptors in modulation of the slow component of delayed rectifier K^+ currents.2005
Author(s)
Lin, C., Nagai, M., Ishigaki, D.Hayakawa, K., Endoh, M., Ishii, K.
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Journal Title
Naunyn-Schmiedeberg's Arch.Pharmacol. 371
Pages: 133-140
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Differential inotropic effects of endothelin-1, angiotensin II, and phenylephrine induced by crosstalk with cAMP-mediated signaling process in dog ventricular myocardium.2004
Author(s)
Chu, L., Norota, I., Yomogida, S., Ishii, K., Endoh, M.
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Journal Title
J.Pharmacol.Sci. 96
Pages: 199-207
Description
「研究成果報告書概要(欧文)」より
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