1991 Fiscal Year Final Research Report Summary
Regulation by beta-adrenoceptor subtypes of cardiac function : Analysis by selective beta agonists
| Project/Area Number |
02454485
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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 |
Biological pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
NAGAO Taku Ph. D. Univ. of Tokyo, Fac. Pharmac. Sci., Professor, 薬学部, 教授 (30217971)
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| Co-Investigator(Kenkyū-buntansha) |
ONO Hedeki Univ. of Tokyo, Fac. Pharmac. Sci., Associate Professor Dep. Toxicol. & Pharmaco, 薬学部, 助教授 (00080200)
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| Project Period (FY) |
1990 – 1991
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| Keywords | beta-adrenoceptor subtypes / beta_1 full agonist / T-0509 / Cyclic AMP compartment / A Kinase / tolerance / L-type CA^<2+> channel / coronary vasodilation |
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| Research Abstract |
This study was aimed to establish T-0509, the catechol derivative of denopamine, as selective beta_1 full agonist and to study functional significance of beta-adrenoceptor subtypes in the ventricular muscle of the heart using selective beta agonists.
First we established the catechol derivative of denopamine (T-0509) as a selective beta_1 full agonist using isolated tissues and radioligand binding assay. T-0509 is almost as potent as isoproterenol and 150 times more selective to beta_1-adrenoceptors than beta_2- adrenoceptors as compared with isoproterenol.
Following results were obtained using T-0509. (1) In the guinea pig heart, we found a subcellular fraction of cAMP which closely relates to the positive inotropic effects (PIE) of various cAMP-dependent agents. In this fraction, A kinase activity also closely related to PIE. (2) In the guinea pig ventricular muscle, PIE of beta full agonists can be explained by an increase in Ca^<2+> current via beta_1-adrenoceptors. (3) The beta full agonist causes desensitization by chronic administration to rats, but the doses used in previous studies were found to be extremely high to study the influence of beta-adrenoceptor subtypes in vivo. We are studying the possibility that selective beta_1 agonist causes weak desensitization as compared with non-selective beta agonists. (4) The beta-adrenoceptor has been shown in canine coronary artery. Wefound the possibility that beta_1 full agonist causes small but significant coronary vasodilation via beta_1-adrenoceptors even in the physiological condition.
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