| Project/Area Number |
12470020
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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 | KYUSHU UNIVERSITY |
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Principal Investigator |
ITO Yushi Graduate School of Medical Sciences, Kyushu University, Professor, 医学研究院, 教授 (80037506)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMOHIGASHI Yasuyuki Graduate School of Sciences, Kyushu University, Professor, 理学研究院, 教授 (00211293)
ONOUE Hitoshi Graduate School of Medical Sciences, Kyushu University, Lecturer, 医学研究院, 講師 (70221166)
INOUE Ryuji Graduate School of Medical Sciences, Kyushu University, Associate Professor, 医学研究院, 助教授 (30232573)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥13,600,000 (Direct Cost: ¥13,600,000)
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| Keywords | novel voltage-gated Ca2+ channels / dihydropyridine-insensitive / peripheral resistant arteriol / blood pressure regulation / vasoactive agent ATP / arylpiperadine / natural toxin / 天然毒 / 新型電位依存性Ca^<2+>チャネル / Caチャネル / Caチャネル拮抗薬 / 血管平滑筋 / 血圧 / 末梢循環 |
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| Research Abstract |
We have recently found that in peripheral resistant arterioles which mainly contribute to regulating the blood pressure and circulation, nifedipine-insensitive (NI-CC) voltage-dependent Ca2+ channels (VDCCs) having entirely distinct biophysical and pharmacological properties from those of hitherto-known VDCCs predominantly exist. The density of NICCs in peripheral circulation appears to increase dramatically towards the periphery, reaching almost 100 %. In this study, we have clarified the following points about these NI-CCs :
(1)NI-CCs showing almost identical properties to those in guinea-pig mesenteric terminal artery have been identified in the same regions of rat and rabbit,
(2) NI-CCs undergo the effective regulation of a major sympathetic neurotransmitter ATP, which potentiates and inhibits NI-CC activities through channel protein phosphorylation by protein kinases A and C at low and higher ATP concentrations, respectively.
(3) Arteriolar diameter or tone under pressurized conditions appears to be at least in part maintained by Ca2+ entry through NI-CC.
(4) Amongst peptide (w-contoxin GVIA, MVIIC, w-agatoxin IVA, SNX482, sFTX3.3) and chemical blockers for VDCCs that are available at present, only mibefradil (Ro40-5967 ; F-Hoffman La Roche) and arylpiperadine derivatives (Snp200001,200002,200003 ; Suntory) completely suppressed NI-CC currents at micromolar concentrations. However, these effects are nonspecific to other types of VDCCs such as T- and R-type VDCCs, the IC50 values being not as three times low as those for the latter two VDCCs. New peptide bloekers selective for NI-CC have not yet been successfully obtained from the screening of natural toxins of snakes, the efforts will be extended to insect and marine toxins in future investigations.
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