1998 Fiscal Year Annual Research Report

ホスフォイノシタイド代謝共役受容体シグナル伝達機構の分子薬理学的分析

Research Project

Project/Area Number	09470021
Research Institution	Yamagata University
Principal Investigator	遠藤政夫山形大学, 医学部, 教授 (40004668)
Co-Investigator(Kenkyū-buntansha)	石幡明山形大学, 医学部, 助手 (40232326) 石井邦明山形大学, 医学部, 助教授 (10184459)
Keywords	交感神経の受容体 / アンジオテンシンII受容体 / エンドセチン受容体 / Caトランジェント / エチルイソプロピルアミロライド / Na^+-H^+交感機構 / KB-R 7943 / Na^+-Ca^<2+>交感機構
Research Abstract	交感神経α受容体、アンジオテンシンIIおよびエンドセリン受容体刺激は、細胞内Ca動員作用と収縮タンパクCa感受性増強作用を発揮する。このCaシグナル調節には、DAGによるPKC活性化と、それに引き続いて起こるNa/H交換機構の活性化による、細胞内アルカリ化とNa蓄積によって二次的に起こる細胞内Ca上昇が寄与していることが考えられる。しかしintact(無傷)な心筋細胞におけるこれらの機序の役割に関しては、使用されるイオン交換機構阻害薬の選択性の低さから仮説の実験的な裏付は困難を極め、一致した見解は得られていない。この仮説を各レベルにおける選択的イオン交換機構遮断薬を用いて検討し以下の点を明らかにした。ウサギ単一心筋細胞におけるエンドセリンによるCaトランジェントの上昇は、Na/Ca交換機構阻害薬のKB-R7943で選択的に(イソプロテレノールによる反応には全く影響を与えることなしに)遮断された。一方エンドセリンによるCa感受性増強作用はKB-R7943による影響を受けにくかった。またアンジオテンシンIIによるCaトランジェントおよびCa感受性増強作用は、選択的Na/H交換機構阻害薬のEIPAおよびKB-R7943により選択的に遮断された。これらの実験結果は、エンドセリンおよびアンジオテンシンII受容体を介するCaシグナルの調節に上記のイオン交換機構の活性化が大きく寄与していることを示唆する。さらにウサギにおけるエンドセリン-1の非典型的薬理学的性状の機序を明らかにするために、ウサギ心筋細胞のETAおよびETB受容体をクローニングした。この非典型的性状はintactな心筋標本における細胞間の相互作用によることを強く示唆する実験データが得られており、さらに実験が進行中である。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] 朱、儀: "Dose nitric oxide contribute to the negative chronotropic and inotropic effects of endothelin-1 in the heart?" Eur.J.Pharmacol.332. 195-199 (1997)
[Publications] 楊黄恬: "Pharmacological evidence for α_1p-adrenoceptors in the rabbit ventriculer myocardium : analysis with BMY 7378." Br.J.Pharmacol.122. 1541-1550 (1997)
[Publications] 楊黄恬: "Species-dependent differences inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in mammalian ventricular myocardium." Br.J.Pharmacol.120. 1497-1504 (1997)
[Publications] 朱儀: "Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle." Am.J.Physiol.273. H119-H127 (1997)
[Publications] 遠藤政夫: "Ca^<2+> signaling in regulation of myocardial contractility." Asia Pacific J.Pharmacol.12. S4-S5 (1997)
[Publications] 遠藤政夫: "The role of phosphoinositide hydrolysis in the receptor-mediated inotropic response of the heart." Asia Pacific J.Pharmacol.12. S11-S13 (1997)
[Publications] Talukder M.A.Hassan: "Pharmacological differentiation of synergistic contribution of L-type Ca^2 channel and Na^+/H^+ exchange angiotensin II in rabbit ventricular myocardium." Naunyn-Shmiedeberg's Arch.Pharmacol.355. 87-96 (1997)
[Publications] Talukder M.A.Hassan: "Differential effects of protein kinase C activators and inhibitore on α-andβ-adrenoceptor-medisted positive inotropic effect in isolated rabbit papillary muscle." J.Cardiovasc.Pharmacol.Ther.2. 159-170 (1997)
[Publications] 遠藤政夫: "Regulation of myocardial contractility by a downstream mechanism." Circ.Res.83. 230-232 (1998)
[Publications] 遠藤政夫: "Changes in intracellular Ca^<2+> mobilization and Ca^<2+> sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells." Jpn.Heart J.39. 1-44 (1998)
[Publications] 遠藤政夫: "Endothelin : receptors subtypes, signal transduction, regulation of Ca^<2+> transients and contractility in rabbit ventricular myocardium." Life Science. 62. 1485-1489 (1998)
[Publications] 渡辺章: "Relationship between the increase in Ca^<2+> transient and contractile force induced by angiotensin II in aequorin-loaded rabbit ventricular myocardium." Cardiovaso.Res.37. 524-531 (1998)
[Publications] 丸屋淳: "Differential regulation of intracellular Ca^<2+> signaling induced by high K^+ and endothelin-1 in signal smooth muscle cells of intact canine bosilarartery : detection by means of conforeal laser mycroscopy" Life Science. in press.
[Publications] 楊黄恬: "Role of Na^+/Ca^<2+> exchange in endothelin-induced increases in Ca^<2+> transient and contractility in rabbit ventricular myocytes : pharmacological analysis with KB-R7943." Br.J.Pharmacol.in press.

1998 Fiscal Year Annual Research Report

ホスフォイノシタイド代謝共役受容体シグナル伝達機構の分子薬理学的分析

Principal Investigator

遠藤 政夫 山形大学, 医学部, 教授 (40004668)

Research Products

[Publications] 朱、儀: "Dose nitric oxide contribute to the negative chronotropic and inotropic effects of endothelin-1 in the heart?" Eur.J.Pharmacol.332. 195-199 (1997)

[Publications] 楊 黄恬: "Pharmacological evidence for α_1p-adrenoceptors in the rabbit ventriculer myocardium : analysis with BMY 7378." Br.J.Pharmacol.122. 1541-1550 (1997)

[Publications] 楊 黄恬: "Species-dependent differences inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in mammalian ventricular myocardium." Br.J.Pharmacol.120. 1497-1504 (1997)

[Publications] 朱 儀: "Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle." Am.J.Physiol.273. H119-H127 (1997)

[Publications] 遠藤 政夫: "Ca^<2+> signaling in regulation of myocardial contractility." Asia Pacific J.Pharmacol.12. S4-S5 (1997)

[Publications] 遠藤 政夫: "The role of phosphoinositide hydrolysis in the receptor-mediated inotropic response of the heart." Asia Pacific J.Pharmacol.12. S11-S13 (1997)

[Publications] Talukder M.A.Hassan: "Pharmacological differentiation of synergistic contribution of L-type Ca^2 channel and Na^+/H^+ exchange angiotensin II in rabbit ventricular myocardium." Naunyn-Shmiedeberg's Arch.Pharmacol.355. 87-96 (1997)

[Publications] Talukder M.A.Hassan: "Differential effects of protein kinase C activators and inhibitore on α-andβ-adrenoceptor-medisted positive inotropic effect in isolated rabbit papillary muscle." J.Cardiovasc.Pharmacol.Ther.2. 159-170 (1997)

[Publications] 遠藤 政夫: "Regulation of myocardial contractility by a downstream mechanism." Circ.Res.83. 230-232 (1998)

[Publications] 遠藤 政夫: "Changes in intracellular Ca^<2+> mobilization and Ca^<2+> sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells." Jpn.Heart J.39. 1-44 (1998)

[Publications] 遠藤 政夫: "Endothelin : receptors subtypes, signal transduction, regulation of Ca^<2+> transients and contractility in rabbit ventricular myocardium." Life Science. 62. 1485-1489 (1998)

[Publications] 渡辺 章: "Relationship between the increase in Ca^<2+> transient and contractile force induced by angiotensin II in aequorin-loaded rabbit ventricular myocardium." Cardiovaso.Res.37. 524-531 (1998)

[Publications] 丸屋 淳: "Differential regulation of intracellular Ca^<2+> signaling induced by high K^+ and endothelin-1 in signal smooth muscle cells of intact canine bosilarartery : detection by means of conforeal laser mycroscopy" Life Science. in press.

[Publications] 楊 黄恬: "Role of Na^+/Ca^<2+> exchange in endothelin-induced increases in Ca^<2+> transient and contractility in rabbit ventricular myocytes : pharmacological analysis with KB-R7943." Br.J.Pharmacol.in press.

遠藤政夫山形大学, 医学部, 教授 (40004668)

[Publications] 楊黄恬: "Pharmacological evidence for α_1p-adrenoceptors in the rabbit ventriculer myocardium : analysis with BMY 7378." Br.J.Pharmacol.122. 1541-1550 (1997)

[Publications] 楊黄恬: "Species-dependent differences inotropic effects and phosphoinositide hydrolysis induced by endothelin-3 in mammalian ventricular myocardium." Br.J.Pharmacol.120. 1497-1504 (1997)

[Publications] 朱儀: "Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle." Am.J.Physiol.273. H119-H127 (1997)

[Publications] 遠藤政夫: "Ca^<2+> signaling in regulation of myocardial contractility." Asia Pacific J.Pharmacol.12. S4-S5 (1997)

[Publications] 遠藤政夫: "The role of phosphoinositide hydrolysis in the receptor-mediated inotropic response of the heart." Asia Pacific J.Pharmacol.12. S11-S13 (1997)

[Publications] 遠藤政夫: "Regulation of myocardial contractility by a downstream mechanism." Circ.Res.83. 230-232 (1998)

[Publications] 遠藤政夫: "Changes in intracellular Ca^<2+> mobilization and Ca^<2+> sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells." Jpn.Heart J.39. 1-44 (1998)

[Publications] 遠藤政夫: "Endothelin : receptors subtypes, signal transduction, regulation of Ca^<2+> transients and contractility in rabbit ventricular myocardium." Life Science. 62. 1485-1489 (1998)

[Publications] 渡辺章: "Relationship between the increase in Ca^<2+> transient and contractile force induced by angiotensin II in aequorin-loaded rabbit ventricular myocardium." Cardiovaso.Res.37. 524-531 (1998)

[Publications] 丸屋淳: "Differential regulation of intracellular Ca^<2+> signaling induced by high K^+ and endothelin-1 in signal smooth muscle cells of intact canine bosilarartery : detection by means of conforeal laser mycroscopy" Life Science. in press.

[Publications] 楊黄恬: "Role of Na^+/Ca^<2+> exchange in endothelin-induced increases in Ca^<2+> transient and contractility in rabbit ventricular myocytes : pharmacological analysis with KB-R7943." Br.J.Pharmacol.in press.