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Studes on the L-arginine-derived, endothelium-independent relaxing factor

Research Project

Project/Area Number 03671054
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionDept. of Pharmacol., Fac. of Pharmaceutical Sci., Univ. of Tokushima

Principal Investigator

MORITOKI Hideki  Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 教授 (10035545)

Co-Investigator(Kenkyū-buntansha) HORIO Shuuhei  Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 助手 (80145010)
FUKUZAWA Kennji  Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 教授 (90035551)
HISAYAMA Tetsuhiro  Univ.of Tokushima, Fac.of Pharmaceutical Sci., 薬学部, 助教授 (70130383)
Project Period (FY) 1991 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1992: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1991: ¥1,100,000 (Direct Cost: ¥1,100,000)
KeywordsL-Arginine / Nitric Oxide / NO synthase / Enzyme induction / Endotoxin / Cytokine / Vasorelaxation / 血管平滑筋由来のNO / NO合成酵素の誘導 / 血管弛緩 / アルギニン / エンドトキシン / サイトカイン / 血管内皮非依存性弛緩 / Arginine / Nitric oxide(NO) / cyclic GMP(cGMP) / NO synthase誘導 / 蛋白合成阻害剤 / 加齢
Research Abstract

1. We examined whether endotoxin contributes to L-arginine-induced relaxation of endothelium-denuded rat thoracic aorta, which apears to be mediated by nitric oxide synthase in the vascular smooth muscle.
2. In the absence of endotoxin, L-arginine induced scarcely any relaxation of the arteries. Treatment of the arteries with endotoxin initiated ralaxation in response to 10 muM L-arginine with lag periods of 2-4 hr, and degree of relaxation increased on repeated application of L-arginine to reach a consistent level in several hours. Increase in the concentration of endotoxin shortened the lag period, enhanced the degree of relaxation and lowered the threshold concentration of L-arginine required to relax the arteries. In endotoxin-primed arteries, L-arginine at concentrations necessary to induce relaxation stimulated cyclic GMP production.
3. Prophylactic appliction of actinomycin D or dexamethasone, which inhibits induction of nitric oxide synthase, prevented induction by endotoxin of L … More -arginine-induced relaxation and cyclic GMP formation. Polymyxin B, which inhibits the action of endotoxin, also prevented development of endotoxin-sensitized relaxation and cyclic GMP formation inducded by L-arginine.
4. When the Krebs solution was prepared using de-ionized water, the amount of endotoxin in the reservoir was above the level required to initiate L-arginine-induced relaxation and cyclic GMP fotmation.
5. These results suggest that endotoxin triggered time-dependent development of L-arginine-induced relaxation by expressing nitric oxide synthase in the vascular smooth muscle.
6. We examined the effects of tyrosine kinase inhibitors on the endotoxin(LPS)-primed, L-arginine-induced relaxation of rat thoracic aorta.
7. Prophylactic application of the tyrosine kinase inhibitors herbimycin A, genistein and erbstatin analog selectively prevented the initiation by LPS of L-arginine-induced relaxation and cyclic GMP formation.
8. These results suggest that tyrosine kinase mediates the L-arginine-induced relaxation of the arteries, probably through protein tyrosine phosphorylation in the LPS-triggered signaling pathway that triggers expression of an inducible NO synthase producing NO. Less

Report

(4 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • 1991 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Moritoki,Hisayama et al.: "Role of endotoxin in L-arginine-induced relaxation of rat thoracic aorta mediated by muscle-derived nitric oxide" Archives Internationales de Pharmacodinamie et de Therapie. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki,Hisayama et al.: "Endothelin-3-induced relaxation of rat thoracic aorta:a role for nitric oxide formation" British Journal of Pharmacology. 108. 1125-1130 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki,Hisayama et al.: "Relaxation of rat thoracic aorta induced by the Ca2+-ATPase inhibitor,cyclopizonic acid through nitric oxide formation." British Journal of Pharmacology. (in press). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki,Hisayama et al.: "Involvement of nitric oxide pathway in the PAF-induced relaxation of rat thoracic aorta." British Journal of Pharmacology. 107. 196-201 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki,Hisayama et al.: "Nitric oxide synthase responsible for L-arginine-induced relaxation of rat aortic rings in vitro may be an inducible type." British Journal of Pharmacology. 107. 361-366 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki,Hisayama et al.: "L-Arginine induces relaxation of rat thoracic aorta possibly through non-endothelial nitric oxide formation" British Journal of Pharmacology. 102. 841-846 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "Role of endotoxin in L-arginine-induced relaxation of rat thoracic aorta mediated by muscle-derived nitric oxide" Arch.int.Pharmacodyn.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "The Ca^<2+>-ATPase inhibitor cyclopiazonic acid induces relaxation of rat thoracic aorta possibly through nitric oxide formation" British.J.Pharmacol.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "Thapsigargin, a Ca^<2+>-ATPase inhibitor, relaxs rat aorta via nitric oxide formation" Life Science. 54. PL153-PL158 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "Endothelin-1-induced relaxation of rat thoracic aorta a role for nitric oxide formation" British.J.Pharmacol.108. 1125-1130 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "Involvement of nitric oxide pathway in the PAF-induced relaxation of rat thoracic aorta." British.J.Pharmacol.107. 196-201 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "Nitric oxide synthase responsible for L-arginine-induced relaxation of rat aortic rings in vitro may be an inducible type" British.J.Pharmacol.107. 361-366 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "Possible mechanisms of age-associated reduction of vascular relaxation caused by atrial natriuretic peptide" EuropeanJ.Pharmacol.210. 61-68 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki, H.et al.: "L-Arginine induces relaxation of rat thoracic aorta possibly through non-endothelial nitric oxide formation" British.J.Pharmacol.102. 841-846 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Moritoki,Hisayama et al.,: "Endothelin-3-induced relaxation of rat thoracic aorta:a role for nitric oxide formation" British Journal of Pharmacology. 108. 1125-1130 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.,: "Role of endotoxin in L-arginine-induced relaxation of rat thoracic aorta mediated by muscle-derived nitric oxide" Archives Internationales de Pharmacodinamie. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.,: "Thapsogargin,a Ca2+-ATPase inhibitor,relaxes rat aorta via nitric oxide formation." Life Science. 54. PL153-PL158 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.,: "Relaxation of rat thoracic aorta induced by the Ca2+-ATPase inhibitor,cyclopizonic acid through nitric oxide formation." British Journal of Pharmacology. (in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.: "Involvement of nitric oxide pathway in the PAF-induced relaxation of rat thoracic aorta." British Journal of Pharmacology. 107. 196-201 (1992)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.: "Nitric oxide synthase responsible for L-arginine-induced relaxation of rat aortic rings in vitro may be an inducible type." British Journal of Pharmacology. 107. 361-366 (1992)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.: "L-Arginine induces relaxation of rat thoracic aorta possibly through non-endothelial nitric oxide formation." British Journal of Pharmacology. 102. 841-846 (1991)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,Hisayama et al.: "Possible association of decrease of ATP-induced vascular relaxation with reduction of cyclic GMP during aging" Archives Internationales de Pharmacodinamie. 320. 35-45 (1991)

    • Related Report
      1993 Annual Research Report
  • [Publications] Moritoki,H., Takeuchi,S.,Hisayama,T., Kondoh,W.: "Nitric oxide synthase responsible for L‐arginine‐induced relaxation of rat aortic rings in vitro may be an inducible type." British Journal of Pharmacology. 107. 361-366 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Moritoki,H., Hisayama,T.,Takeuchi,S., Miyano,H.,Kondoh,W: "Involvement of nitric oxide pathway in PAF‐induced relaxation of rat thoracic aorta." British Journal of Pharmacology. 107. 196-201 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Moritoki,H., Yoshikawa,T.,Hisayama,T., Takeuchi,S.: "Possible mechanisms of age‐associated reduction of vascular relaxation caused by arterial natriuretic peptide." European Journal of Pharmacology. 210. 61-68 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Moritoki,H., Miyano,H.,Takeuchi.S., Yamaguchi,M.,Hisayama,T., Kondoh,W.: "Endothelin‐3‐induced relaxation of rat thoracic aorta:a role for nitric oxide formation." British Journal of Pharmacology. 印刷中. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] 守時 英喜: "血管平滑筋由来のnitric oxide(MDNO) -L‐アルギニンの血管作用-" 血管と内皮. 2. 32-40 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] H.Moritoki,H.Ueda,T.Yamamoto,T.Hisayama and S.Takeuchi: "LーArginine induces relaxation of rat aorta possibly through nonーendothelial nitric oxide formation." Br.J.Pharmacol.102. 841-846 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] H.Ueda and H.Moritoki: "Possible association of decrease in ATPーinduced vascular relaxation with reduction of cyclic GMP during aging." Arch.Int.Pharmacodyn.,. 310. 35-45 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] H.Moritoki,T.Hisayama and H.Ueda: "Adenosineーinduced dilation of rat thoracic aorta is mediated by cyclic GMP and is ageーdependent." Nucleosides and Nucleotides,. 10. 1231-1233 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] S.Imai and M.Nakazawa(eds.),H.Moritoki: "Evidence for the involvement of cyclic GMP in adenosineーinduced vasodilation." Role of adenosine and adenine nucleotides in the biological system,(Elsevier Science Publishers BV). 218-225 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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