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Cardiorespiratory Regulation in Endothelin- 1 Gene Knockedout Mice

Research Project

Project/Area Number 06670047
Research Category

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

Allocation TypeSingle-year Grants
Research Field General physiology
Research InstitutionTHE UNIVERSITY OF TOKYO

Principal Investigator

KUWAKI Tomoyuki  The University of Tokyo, Department of Physiology, Faculty of Medicine, Research Associate, 医学部(医), 助手 (80205260)

Co-Investigator(Kenkyū-buntansha) KUMADA Mamoru  The University of Tokyo, Department of Physiology, Faculty of Medicine, Professo, 医学部(医), 教授 (00110487)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1994: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsEndothelin-1 / Knockedout Mice / Hypertension / Respiratory Reflex / Cardiorespiratory Center / Power Spectral Analysis / New Born Mice / 延髄循環呼吸中枢
Research Abstract

We successfully developed endothelin (ET)-1 gene knckout mice and used them in the following experiment. 1) We were able to obtain stable recordings of the mice's blood pressure and heart rate, without any restriction nor anesthesia, for more than 2 hours. Obtained large quantity of data was handled with an aid of a computer. 2) By body plethysmography, we measured ventilation movement and its reflex change to hypoxia or hypercapnia in mature and new born conscious mice. 3) We recorded phrenic nerve discharges in urethane-anesthetized adult mice and measured their reflex change in response to hypoxia or hypercapnia. 4) Finally, we tested whether power spectral analysis of blood pressure fluctuations could be used in the mice as an evaluation method of autonomic nerve function.
As a result, homozygotes that completely lost ET-1 gene died soon after birth by abnormal formation of craniofacial tissues. On the other hand, heterozygotes of which plasma concentration of ET-1 was about half of … More the normal mice showed significantly higher blood pressure than in the controls. In ET-1 deficient heterozygous mice, arterial pO_2 was significantly lower, pCO_2 tended to be higher and pH tended to be lower than in wild-type littermates. When these conscious mice breathed room air, respiratory minute volume and rate were not different between the two groups, although reflex increase to hypoxia or hypercapnia was significantly attenuated in ET-1^<+/-> heterozygotes. Since impaired reflex responses were also evident by recording phrenic nerve discharges, the cause of ventilatory impairment lay, at least in part, in the nervous system. Furthermore, in homozygotes that were delivered by cesarian sections and tracheotomized, reflex increase in ventilation was severely attenuated. Thus ET-1 plays a pivotal role in reflex control of respiration. Abnormality of breathing regulation in ET-1 deficient mice may account for the elevated blood pressure. In fact, similar cardiorespiratory abnormality was suggested by power spectrum analysis of blood pressure fluctuations.
In summary, ET-1 participates in development and cardiorespiratory regulation in mice. This is an important and new finding and widens the suggested notion that ET-1 is not a mere vasoconstrictor but a playr of a variety of physiological roles. Moreover, it becomes clear that many of the techniques to study autonomic nervous function in the whole animal can be used in such a small animal as mouse with some modifications. Less

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] T. KUWAKI: "Impaired ventilatory responsez to hypoxia and hypercapnia in mutant mice deficient in endothelin-1" Amerian Journal of Physiology. (印刷中). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. KUWAKI: "Role of endothelin In contral cardiorespiratory control: Modern and classical approacher" News in Physiologial Sciences. 10. 228-233 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. KURIHARA: "Elevated blood pressure and craniofacial abnormalities in mice deficient in-endothelin-1" Nature. 368. 703-710 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. KUWAKI: "Endothelin in the brain and its effect on central control of the circulation and other functions" Japanese Journal of Physiology. 44. 1-18 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K. MAEMURA: "Gene expression of endothelin isoforms and receptors in endothelin-1-knockedout mice" Journal of Cardiovascular Pharmacology. 26. S17-S21 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. KURIHARA: "Impaired development of the thyroid and thymus in endothelin-1-knockedout mice" Journal of Cardiovasular Pharmacology. 26. S13-S16 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 桑木共之: "動脈圧受容器反射と高血圧" 医学の歩み. 169. 509-514 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 桑木共之: "エンドセリンと中枢神経系" 医学の歩み. 170. 383-387 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 桑木共之: "自律神経機能とエンドセリン" 自律神経. 31. 257-261 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 熊田 衛: "心臓血管中枢の局在と神経機構" 自律神経. 31. 347-350 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwaki, W.H.Cao, Y.Kurihara, H.Kurihara, G.Y.Ling, M.Onodera, K.H.Ju, Y.Yazaki & M.Kumada: "Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1" Am J Physiol. (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwaki, Y.Kurihara, H.Kurihara, Y.Yazaki & M.Kumada: "Role of endothelin in central cardiorespiratory control : Modern and classical approaches" News Physiol Sci. 10. 228-233 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Kurihara, H.Kurihara, H.Suzuki, T.Kodama, K.Maemura, R.Nagai, H.Oda, T.Kuwaki, W.-H.Cao, N.Kamada, K.Jishage, Y.Ouchi, S.Azuma, Y.Toyoda, T.Ishikawa, M.Kumada & Y.Yazaki: "Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1" Nature (Lond.). 368. 703-710 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kuwaki, W.-H.Cao, & M.Kumada: "Endothelin in the brain and its effect on central control of the circulation and other functions" Jpn J Physiol. 44. 1-18 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Maemura, H.Kurihara, Y.Kurihara, T.Kuwaki, M.Kumada & Y.Yazaki: "Gene expression of endothelin isoforms and receptors' in endothelin-1-knockedout mice" J.Cardiovasc.Pharmacol.26 (suppl.3). S17-S21 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Kurihara, H.Kurihara, K.Maemura, T.Kuwaki, M.Kumada & Y.Yazaki: "Impaired development of the thyroid and thymus in endothelin-1-knockedout mice" J.Cardiovasc.Pharmacol. 26 (suppl.3). S13-S16 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary

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Published: 1994-04-01   Modified: 2016-04-21  

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