| Project/Area Number |
03454142
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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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 Univ.Sch.of Med. : Professor, 医学部, 教授 (40004668)
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| Co-Investigator(Kenkyū-buntansha) |
石幡 明 山形大学, 医学部, 助手 (40232326)
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| Project Period (FY) |
1991 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1993: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1992: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1991: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | alpha_1-Adrenoceptor / Endothelin / Angiotensin / PI hydrolysis / Positive inotropic effect / Protein kinase C / alpha_1-Receptor subtype / Rabbit papillary muscle / α_<1A>受容体 / α_<1B>受容体 / (+)ニグルジピン / 5-メチルウラピジル / クロルエチルクロニジン / ホルボールエステル / 心筋α受容体 / イノシト-ル燐脂質代謝促進 / ホルボ-ルエステル |
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| Research Abstract |
The signal transduction process subsequent to activation of myocardial alpha_1-adrenoceptors has been further complicated by the discovery of subtypes, alpha_<1A>, alpha_<1B> and alpha_<1C> whereas the functional role of alpha _<1C> in cardiac function is unknown at the moment. The present study was carried out to elucidate intracellular process mediated by cardiac alpha_1-adrenoceptors. Results obtained can be summarized as follows : (1)In the rabbit ventricle ca. 60% of alpha_1-adrenoceptors belong to alpha_<1B> subtype, which is coupled to the positive inotropic effect (PIE) and PI hydrolysis and is effectively antagonized by chlorethylclonidine (CEC). CEC at 0.1-10 uM inhibited the PIE of phenylephrine mediated by alpha_1-adrenoceptors in a concentration-dependent manner. (2)In the rabbit ventricle ca. 40% of alpha_1-receptors belong to alpha_<1A> subtype. There appear to be further two subclasses in this subtype : (1)WB 4101-sensitive one, coupled to PI hydrolysis and PIE ; (2) (+)-niguldipine-sensitive one, coupled to PIE without acceleration of PI hydrolysis. Denopamine and HV723 (in low concentration) inhibit selectively the (+)-niguldipine-sensitive subtype. (3)Activation of endothelin and angiotensin receptor in rabbit heart accelerates PI hydrolysis as alpha_1 stimulation does. In the present study it was found that the response to activation of these receptors showed a remarkable similarity to each other in following respects : (1) the PIE was associated with prolongation of isometric twitch contractions ; (2) the concentration-and time-dependent change in PIE and PI hydrolysis in response to receptor activation showed an excellent correlation ; (3) phorbol 12,13-dibutyrate that activates protein kinase C consistently inhibited the PIE and PI hydrolyis elicited through these receptors. These findings strongly indicate that PI hydrolysis may mediated the PIE induced by activation of
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