| Project/Area Number |
12670084
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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 |
General pharmacology
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| Research Institution | Fukui Medical University |
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Principal Investigator |
URAMATSU Ikunobu Fukui Medical University, Professor Department of Pharmacology, 医学部, 教授 (10111965)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Takashi Fukui Medical University, Assistant Professor Department of Pharmacology, 医学部, 助手 (40313746)
TANIGUCHI Takanobu Fukui Medical University, Associate Professor Department of Pharmacology, 医学部, 助教授 (60217130)
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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 |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | α_1adrenoceptor / inverse agonist / neutral antagonist / tolerance_ / supersensitivity / constitutive activity / 相互作用 |
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| Research Abstract |
Many G-protein-coupled receptors including α adrenoceptors are known to be constitutively active without agonist, which is inhibited by inverse agonist but not by neutral antagonist. When we administer inverse agonist and neural antagonist, how are the constitutively active reveptors affected by the drugs? We first identified inverse agonists and neutral antagonists of α_1 adrenoceptors and examined their effects on the constitutively activities in vitro. Thereafter, the chronic effects on native α_1 adrenoceptors were examined in vivo.
In the CHO cells expressed a, adrenoceptor mutants, prazosin was identified as a common inverse agonist for α_1a, α_1b, and α_1d adrenoceptor subtypes, while KMD-3213 was detected as an α_1a selective neutral antagonist. Treatment with prazosin reduced the basal IP_3 level and increased the receptor density (upregulation). On the other hand, KMD-3212 neither changed the basal IP_3 level nor receptor density, but inhibited the upregulation induced by prazosin.
In rats, chronic administration of prazosin produced upregulation of α_1a and α_1b subtypes in heart and α_1b subtype in spleen. However, chronic administration of KMD-3213 failed to change the receptor density in heart and spleen. The rat thoracic aorta after chronic administration of prazosin but not KMD-321 3 was sensitive to phenylephrine as compared with control, resulting in supersensitivity in the contractile responses.
The present study suggests that constitutive activity of native receptors varies among tissues or subtypes and that the effects of inverse agonist and neutral antagonist depend on the different levels of constitutive activity. Tolerance may develop in constitutively active receptors after chronic treatment with inverse agonist but not neutral antagonist.
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