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1997 Fiscal Year Final Research Report Summary

Development of the modulator drug specifically targeting biomechanical reaction in the circulatory system and the application for experimental therapeutics.

Research Project

Project/Area Number 08557139
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionUniversity of Shizuoka

Principal Investigator

NAKAYAMA Koichi  Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Shizuoka, Professor, 薬学部, 教授 (50112769)

Co-Investigator(Kenkyū-buntansha) TANABE Yoshiyuki  Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Sh, 薬学部, 助手 (10275109)
OBARA Kazuo  Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Sh, 薬学部, 講師 (60117611)
ASANO Toshio  Laboratory for Pharmaceutical Research, Institute for Life Science Research, Asa, 開発薬理研究所, 主任研究員
ISHII Kunio  Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Sh, 薬学部, 教授 (90137993)
TAKEISHI Keiichi  School of Food and Nutritional Sciences, University of Shizuoka, Professor, 食品栄養科学部, 教授 (90012608)
Project Period (FY) 1996 – 1997
Keywordsmechano-transduction / biomechanics / tyrosine kinase inhibitor / protein tyosyl phosphorylation / cardiovascular system / myogenic contraction / hemodynamics / stretch / pressure
Research Abstract

Purpose The cardiovascular response to hemodynamic/biomechanical stimuli, including pressure and flow, is a type of physical reception and a subsequent intra/inter cellular signaling in the heart and blood vessels. Pathophysiological conditions, such as vasospasm, hypertension, and myocardial hypertrophy, are also caused by the abnormal biomechanical stimuli. In order to elucidate the mechanism for mechano-transduction and to develop a new modulator of biomechanical reaction in the cardiovascular system, the following experiments were undertaken : 1) intra/intercellular signaling mechanism of arterial tissues and cells isolated from brain artery and lung in response to pressure and stretch with the special regard to protein tyrosyl phosphorylation, intracellular Ca2+ concentration, and mechanical activity. 2) Search for a new modulator of the response to hemodynamic stimuli. 3) Experimental therapeutics in the monocrotaline-induced pulmonary hypertensive rats. Results and discussions A … More s to the mechanism for mechano-transduction, the following process could be suggested : The membrane depolarization and activation of L-type Ca2+ channels through protein tyrosyl phosphorylation of the mechano-gated channel triggers the mechanical activity. Morcover, platelet-derived growth factor receptor- b chain, a receptor type of tyrosine kinase, and an intracellular messenger, such as Rho, a low molecular GTP-binding protein, are specifically involved in the signaling of mechano-transduction. Future prospect The cardiovascular response to hemodynamic stimuli touch the core of up to-date problems, including regulation of blood pressure and flow, myogenic tone, mechano-gated ion channels, shear stress and endothelial function, and pathophysiological implications of high and low shear stress and hemodynamic overload. Our present studies will surely open the way to an era for the development of new cardiovascular drugs with a novel mechanism of action, and our general principle will improve the knowledge about the cardiovascular system in health and disease. Less

  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [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薬ファスジル(AT877)の血液凝固時間および血漿板に対する作用。" 薬理と治療 (Jpn.Pharmacol.Ther.),. 24,. 799-801 (1996)

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  • [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 研究成果報告集. 12,. 107-115 (1996)

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  • [Publications] Koichi Nakayama, Kiichiro Ueta, Yoshio Tanaka, Yoshiyuki Tanabe and Kunio Ishii: "Stretch-induced contraction of rabbit isolated pulmonary artery and the involvement of endothelium-derived thromboxane A_2." Br.J.Phamacol.122. 199-208 (1997)

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  • [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.330. 55-63 (1997)

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  • [Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama: "Flow-dependent regulation of nitric oxide formation in the isolated canine mesenteric arterial bed." Jpn.J.Pharmacol.74. 275-280 (1997)

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  • [Publications] Jane M.Lalli, Kazuo Obara and Richard J.Paul: "Vanadate oxidation activates contraction in skinned smooth muscle without myosin light chain phosphorylation." Am.J.Physiol.41. C278-C288 (1997)

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  • [Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama: "Flow regulates vasodilator responses to acetylcholine in the isolated canine mesenteric arterial bed." Biol.Pharm.Bull.20. 568-570 (1997)

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  • [Publications] Kazuo Obara, Peggy S.Bowman, Yukisato Ishida and Richard J.Paul: "Effects of hypoxia on [Ca^<2+>]_i, pH_i and myosin light chain phosphorylation in guinea-pig taenia cacci." J.Physiol.503. 427-433 (1997)

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  • [Publications] Yoshiyuki Tanabe, Chie Kohchi, Namiko Kitahara-Tanabe, Den'ichi Mizuno, Gen Ichiro Soma: "Involvement of 26-kDa membrane-bound tumour necrosis factor precursor in bidirectional feedback regulation on 17-kDa tumour necrosis factor production after stimulation by lipopolysaccharide." Cytokine. 10. 82-92 (1998)

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

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  • [Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama: "Infusion of pressor agents selectively attenuate depressor response to Ach in anethetized dogs." Am.J.Physiol.271. H273-H281 (1996)

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  • [Publications] Kazuo Obara, Pawel T.Szymanski, Terence Tao and Richard J.Paul: "Effect of calponin on isometric force and shortening velocity in permeabilized tacnia coli smooth muscle." Am.J.Physiol.270. C481-C487 (1996)

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  • [Publications] Tsutomu Nakahara, Kunio Ishii, Yoshio Tanaka and Koichi Nakayama: "Involement of neurohumoral factors in the pressor mecchanism of NG-nitro-L-arginine." Eur.J.Pharmacol.287. 49-56 (1995)

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  • [Publications] Yoshio Tanaka, Tohru Nakazawa, Hiromi Ishiro, Michihiro Saito, Hisayuki Uneyama, Scinosuke Iwata, Kunio Ishii and Koichi Nakayama: "Ca^<2+> handing mechanisms underlying neuropeptide Y-induced contraction in canine basilar artery." Eur.J.Pharmacol.289. 59-66 (1995)

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  • [Publications] Kazuo Obara, Gordana Nikccvic, Lidija Pcstic, Grzegorz Nowak, Donald D.Lorimer, Vince Guerricro, Jr., Elliot L.Elson, Richard J.Paul and Primal de Lancrolle: "Fibroblast contractility without an increase in basal myosin light chain phosphorylation in wild type cells and cells expressing the catalytic domain of myosin light chain kinase." J.Biol.Chem.270. 18734-18737 (1995)

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  • [Publications] Tsutomu Nakahara, Kunio Ishii, Kenichiro 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)

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  • [Publications] Hong Sheng, Kunio Ishii, Ulrich Fostermann and Ferid Murad: "Mechanism of bradykinin-induced cyclic GMP accumulation in bovine tracheal smooth muscle." Lung.73. 373-383 (1995)

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  • [Publications] Yoshio Tanaka, Hiromi Ishiro, Tohru Nakazawa, Michihiro Saito, Kunio Ishii 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.Pharmac.26. 855-864 (1995)

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  • [Publications] Hisayuki Uneyama, Yoshio Tanaka, Seinosuke Iwata, Tsuneo Ishiguro and Koichi Nakayama: "Pharmacological characteristics of the canine ccrrcbrovascular cinstriction produced by neuropeptide Y." Biol.Pharm.Bull.18. 501-506 (1995)

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  • [Publications] Satoh, Y.Yamamoto, Y.Toshima, Ikegaki, T.Asano, Y.Suzuki and M.Shibuya: "Fasudil, a protein kinase inhibitor, prevents the development of endothelial injury and neutrophil infiltration in a two- haemorrhage canine model." J.Clin.Neurosci.in press. (1998)

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  • [Publications] Yoshinori Toshima, Shin-ichi satoh, Ichiro Ikegaki, Toshio Asano, Yoshio Suzuki and Masato Shibuya: "Thromboxane A2 synthetase inhibitor failed to ameliorate the arterial narrowing during the chronic phase of ccrebral vasospasm." Life Sci.61(14). 1371-1377 (1997)

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  • [Publications] Naoki Katsumata, Hiroaki Shimokawa, Minoru Seto, Toshiyuki Kozai, Tohru Yamawaki, Kouichi Kuwata, Kensuke Egashira, Ichiro Ikegaki, Toshio Asano, Yasuharu Sasaki, Akira Takeshita: "Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-Ib." Circulation. 96. 4357-4363 (1997)

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

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  • [Publications] Maki Wakabayashi, Hideyuki Katai, Nobuyuki Horie and Keiichi Takeishi: "Cloning of the monkey thymidylate synthase gene and characterization of regulatory sequences in the promoter region." Nucleic Acids Symposium Series. 35. 227-228 (1996)

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  • [Publications] Nobuyuki Horie and Keiichi 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.272. 18357-18381 (1997)

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Published: 1999-03-16  

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