1996 Fiscal Year Annual Research Report

循環系におけるバイオメカニクス反応の特異的制御薬の開発と実験治療学的応用について

Research Project

Project/Area Number	08557139
Section	試験
Research Institution	University of Shizuoka
Principal Investigator	中山貢一静岡県立大学, 薬学部・薬理学教室, 教授 (50112769)
Co-Investigator(Kenkyū-buntansha)	竹石桂一静岡県立大学, 食品栄養科学部, 教授 (90012608) 石井邦雄静岡県立大学, 薬学部, 助教授 (90137993) 浅井敏雄旭化成工業(株), 開発薬理研究所, 主任研究員
Keywords	バイオメカニクス / 循環系 / チロシンキナーゼ阻害薬 / 物理受容・応答 / 細胞内情報伝達 / 接着班キナーゼ活性 / 血管収縮 / 実験治療学
Research Abstract	循環系におけるバイオメカニクスの研究は、心臓・血管系において生理・病態に重要なる意義を有する血流、血圧等の血行力学刺激に対する細胞反応機序の解明とその薬理学的制御を目指す。本研究代表者はその研究実績を踏まえて"メカニカルストレスと細胞反応:薬理・生理学立場でのアプローチ"という題目で70回日本薬理学会総会シンポジウム(1997年3月、幕張メッセ、千葉)を組織し、本研究を牽引している。得られた成果は以下に要約できる。 1)バイオメカニクス反応の得意的制御薬の開発:血行力学因子による刺激は血管組織を構成する平滑筋・内皮細胞等の細胞接着機構に著しい影響をおよぼす。接着班を形成するチロシンキナーゼの一種である接着班キナーゼ、並びにインテグリンが、細胞外マトリクスと相互作用し、伸展刺激の感受部位(センサー)として機能する可能性を想定した。このセンサー機能を抑制するチロシンキナーゼ阻害薬を種々探索した。その結果、内腔圧の増加等の機械的刺激に依存した血管の筋原性収縮機構において、ハービマイシンA感受性チロシンキナーゼが特異的に関与する事を見いだした。 2)バイオメカニクス反応におけるにおけるチロシンリン酸化の役割の解明:、分子生物学的手法を用いて1)チロシンキナーゼ分子種の同定、2)機械的刺激に応答した血管収縮機構におけるチロシンリン酸化の測定を行っている。さらに実験的肺高血圧症ラットを用いた病態動物の血管反応におけるチロシンキナーゼの役割の検討が進行中である。 3)ストレッチ誘発血管収縮反応の生物学的研究とミオシン軽鎖リン酸化:緩徐伸展刺激誘発収縮張力とミオシン軽鎖リン酸化には乖離がある。機械的刺激が脱リン酸化機構の抑制をもたらす可能性を示唆した。これらの研究の今後の発展が大いに期待できる。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Yoshio Tanaka, Tohru Nakazawa, Hiromi Ishiro, Michiyasu Saito, Kunio Ushii and Koichi Nakayama.: "Ca^<2+> handing mechanisms underlying neuropeptide Y-induced contraction in canine cerebral artery." Eur. J. Pharmacol. Mol. Sec.289. 59-66 (1995.)
[Publications] Yoshio Tanaka, Tohru Nakazawa, Hiromi Ishiro, Michiyasu Saito, Kunio Ushii and Koichi Nakayama.: "Potentiation by endothelin-1 of Ca^<2+> sensitivity of contractile elements depends on Ca^<2+> influx through L-type Ca^<2+> channels in the canine cerebral artery." Gen. Pharmacol.26. 855-864 (1995.)
[Publications] Hisayuki Uneyama, Yoshio Tanaka, Seinosuke Iwata, Tsuneo Ishiguro and Koichi Nakayama.: "Pharmacological chatacteristics of the canine cerebrovascular constriction produced by neuropeptide Y." Biol. Pharmaceuti. Bull.18. 501-506 (1995.)
[Publications] Koichi Nakayama. Tohru Nakazawa, Yoshihisa Fukuta, and Yoshio Tanaka.: "Stereo-selective calcium antagonistic and binding properties of the enantioments of lemildipine in vascular tissue of pigs and dogs." Arzneim. Forsch./Drugs Res.46 (II). 1045-1053 (1996.)
[Publications] Koichi Nakayama.: "Pharmacological profile and therapeutic perspectives of semotiadil fumarate (SD-3211), a novel benzothiazine Ca^<2+> antagonist. Cardiovasc." Drug. Rev.14. 97-134 (1996.)
[Publications] Naohiro Masumoto, Koichi Nakayama, Akihiro Oyabe, Mayumi Uchino, Kunio Ishii, Kazuo Obara and Yoshiyuki Tanabe.: "Specific attenuation of the pressure-induced contraction of rat cerebral artery by herbimycin A." Eur. J. Pharmacol.(in press.).
[Publications] Koichi Nakayama, Kiichiro Ueta, Yoshio Tanaka, Yoshiyuki Tanabe & Kunio Ishii.: "Stretch-unduced contraction of isolated rabiit pulmonary artery is produced by endothelium-derived thromboxane A2." Brit. J. Pharmacol.(in press.).
[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka, and Koichi Nakayama.: "Flow regulates vasodilator responses to acetylcholine in the isolated canine mesenteric arterial bed." Biol. Pharmacol. Bull.(in press.).
[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka, and Koichi Nakayama.: "Flow-dependent regulation of NO formation in the isolated canine mesenteric arterial bed." Japan. J. Pharmacol.(in press.).
[Publications] K. Sako, Y. Yonemasu, M. Tsutiya, T. Asano.: "HA 1077 : a novel intrecellular calcium antagonist. 1. Pharmacology." CNS Drug Reviews. 2 (2). 160-174 (1996.)
[Publications] S. Satoh, I. Ikegaki, Y. Suzuki, T. Asano, M. Shibuya, H. Hidaka.: "Neuroprotective properties of a protein kinase inhibitor against ischaemia-induced neuronal damage in rats and gerbils." Br. J. Pharmacol.118. 1592-1596 (1996.)
[Publications] 生垣一郎,佐藤多恵、佐多美奈子、浅野敏雄: "蛋白リン酸化酵素阻害剤ファスジル(AT877)の血液凝固時間および血小板凝集に対する作用" 薬理と治療. 24 (4). 121-123 (1996.)
[Publications] Tsutomu Nakahara, Kunio Ishii, Ken-Ichiro Iwamoto and Koichi Nakayama.: "Differential significance of nitric oxide in hypotensive mechanisms of acetylcholine and histamine in dogs." Res. Commun. Mol. Path. Pharmacol.89. 77-84 (1995.)
[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama.: "Involvement of neurohumoral factors in the pressor mechanism of N^G-nitro-L-arginine" Eur. J. Pharmacol.287. 49-56 (1995.)
[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama.: "Infusions of pressor agents selectively attenuate depressor responses to ACh in anesthetized dogs." Am. J. Physiol.271 (Heart Ciec. Physiol. 40). H273-H281 (1996.)
[Publications] 竹石桂一: "白血病細胞の分化誘導時における細胞増殖必須遺伝子の発現抑制機構の解析" 薬学の進歩. 12. 107-115 (1996.)
[Publications] M. Wakabayashi, H. Katai, N. Horie, K. Takeishi.: "Clonong of the monkey thymidylate synthase gene and characterization of regulatory sequences in the promoter region" Nucleic Acids Symp. Series. No.35. 227-228 (1996.)
[Publications] Nobuaki Horie and Kiichi Takeishi.: "Identification of functional elements in the promoter region of the human gene for thymidylate synthase and nuclear factors that regulate the expression of the gene." J. Biol. Chem., resubmitted after revision.(1997.)

1996 Fiscal Year Annual Research Report

循環系におけるバイオメカニクス反応の特異的制御薬の開発と実験治療学的応用について

Principal Investigator

中山 貢一 静岡県立大学, 薬学部・薬理学教室, 教授 (50112769)

Research Products

[Publications] Yoshio Tanaka, Tohru Nakazawa, Hiromi Ishiro, Michiyasu Saito, Kunio Ushii and Koichi Nakayama.: "Ca^<2+> handing mechanisms underlying neuropeptide Y-induced contraction in canine cerebral artery." Eur. J. Pharmacol. Mol. Sec.289. 59-66 (1995.)

[Publications] Hisayuki Uneyama, Yoshio Tanaka, Seinosuke Iwata, Tsuneo Ishiguro and Koichi Nakayama.: "Pharmacological chatacteristics of the canine cerebrovascular constriction produced by neuropeptide Y." Biol. Pharmaceuti. Bull.18. 501-506 (1995.)

[Publications] Koichi Nakayama. Tohru Nakazawa, Yoshihisa Fukuta, and Yoshio Tanaka.: "Stereo-selective calcium antagonistic and binding properties of the enantioments of lemildipine in vascular tissue of pigs and dogs." Arzneim. Forsch./Drugs Res.46 (II). 1045-1053 (1996.)

[Publications] Koichi Nakayama.: "Pharmacological profile and therapeutic perspectives of semotiadil fumarate (SD-3211), a novel benzothiazine Ca^<2+> antagonist. Cardiovasc." Drug. Rev.14. 97-134 (1996.)

[Publications] Naohiro Masumoto, Koichi Nakayama, Akihiro Oyabe, Mayumi Uchino, Kunio Ishii, Kazuo Obara and Yoshiyuki Tanabe.: "Specific attenuation of the pressure-induced contraction of rat cerebral artery by herbimycin A." Eur. J. Pharmacol.(in press.).

[Publications] Koichi Nakayama, Kiichiro Ueta, Yoshio Tanaka, Yoshiyuki Tanabe & Kunio Ishii.: "Stretch-unduced contraction of isolated rabiit pulmonary artery is produced by endothelium-derived thromboxane A2." Brit. J. Pharmacol.(in press.).

[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka, and Koichi Nakayama.: "Flow regulates vasodilator responses to acetylcholine in the isolated canine mesenteric arterial bed." Biol. Pharmacol. Bull.(in press.).

[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka, and Koichi Nakayama.: "Flow-dependent regulation of NO formation in the isolated canine mesenteric arterial bed." Japan. J. Pharmacol.(in press.).

[Publications] K. Sako, Y. Yonemasu, M. Tsutiya, T. Asano.: "HA 1077 : a novel intrecellular calcium antagonist. 1. Pharmacology." CNS Drug Reviews. 2 (2). 160-174 (1996.)

[Publications] S. Satoh, I. Ikegaki, Y. Suzuki, T. Asano, M. Shibuya, H. Hidaka.: "Neuroprotective properties of a protein kinase inhibitor against ischaemia-induced neuronal damage in rats and gerbils." Br. J. Pharmacol.118. 1592-1596 (1996.)

[Publications] 生垣一郎,佐藤多恵、佐多美奈子、浅野敏雄: "蛋白リン酸化酵素阻害剤ファスジル(AT877)の血液凝固時間および血小板凝集に対する作用" 薬理と治療. 24 (4). 121-123 (1996.)

[Publications] Tsutomu Nakahara, Kunio Ishii, Ken-Ichiro Iwamoto and Koichi Nakayama.: "Differential significance of nitric oxide in hypotensive mechanisms of acetylcholine and histamine in dogs." Res. Commun. Mol. Path. Pharmacol.89. 77-84 (1995.)

[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama.: "Involvement of neurohumoral factors in the pressor mechanism of N^G-nitro-L-arginine" Eur. J. Pharmacol.287. 49-56 (1995.)

[Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama.: "Infusions of pressor agents selectively attenuate depressor responses to ACh in anesthetized dogs." Am. J. Physiol.271 (Heart Ciec. Physiol. 40). H273-H281 (1996.)

[Publications] 竹石桂一: "白血病細胞の分化誘導時における細胞増殖必須遺伝子の発現抑制機構の解析" 薬学の進歩. 12. 107-115 (1996.)

[Publications] M. Wakabayashi, H. Katai, N. Horie, K. Takeishi.: "Clonong of the monkey thymidylate synthase gene and characterization of regulatory sequences in the promoter region" Nucleic Acids Symp. Series. No.35. 227-228 (1996.)

[Publications] Nobuaki Horie and Kiichi Takeishi.: "Identification of functional elements in the promoter region of the human gene for thymidylate synthase and nuclear factors that regulate the expression of the gene." J. Biol. Chem., resubmitted after revision.(1997.)

中山貢一静岡県立大学, 薬学部・薬理学教室, 教授 (50112769)