高血圧発症における延髄心臓血管中枢の微小循環機能障害の役割

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26670413
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: 白井 幹康 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (70162758)
• Co-Investigator(Kenkyū-buntansha): 土持 裕胤 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60379948)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 循環器・高血圧 / 交感神経活動 / 心臓血管中枢 / 延髄微小循環 / 間歇的低酸素 / 肺交感神経活動

Outline of Annual Research Achievements

麻酔下ラットにSPring-8微小血管造影法を応用して椎骨動脈造影による延髄微小循環の可視化を行い、高血圧を発症する前の生後4か月の高血圧自然発症ラット(SHR)と対照ラットで微小循環応答を比較した。10% O2の吸入に対して、延髄細動脈は、対照では拡張したが、SHRでは収縮した。アンジオテンシン-II及びノルアドレナリンの静脈内投与に対して、いずれのラットの延髄細動脈も同程度に収縮した。一酸化窒素合成阻害薬に対して、やはり同程度に収縮した。以上より、高血圧発症前のSHRの延髄細動脈応答異常は、低酸素に対して特異的に生じることが示唆された。
昨年度、SHR及びDahl食塩感受性ラットで、高血圧発症過程で腎及び腰部交感神経活動は変化しないことを見出した。本年度、睡眠時無呼吸症候群モデルラット（間歇的低酸素＋高炭酸ガス負荷を8時間/日、1か月間持続）で調べた結果、血圧上昇に並行して腎及び腰部交感神経活動が増大することが分かった。
他方、間歇的低酸素を8時間/日、1か月持続したラットでは、肺交感神経活動は亢進したが、肺循環の昇圧は生じなかった。肺血管に対する低酸素の直接的効果は血管収縮であることを考慮すると、この間歇的低酸素ラットでの肺交感神経活動亢進は肺循環に対して降圧効果を有するか、少なくとも昇圧効果はないものと考えられた。そこで、間歇的低酸素負荷と並行して脳室内へのβ1遮断薬投与による交感神経活動抑制あるいは静脈内へのβ2遮断薬投与を行った。その結果、肺循環の昇圧が生じたことから、この肺交感神経活動増大は、肺循環に対して降圧効果を有することが示唆された。
以上から、高血圧発症に交感神経活動の増大がどの程度重要かは不明であるが、延髄の虚血に対する循環異常が交感神経増大を起こす可能性が考えられた。また、体循環と異なり肺循環では交感神経活動増大が降圧に働くことが示唆された。

Research Products

• [Int'l Joint Research] Dept. of Physiology, Monash University(Australia)
  • Country Name: Australia
  • Counterpart Institution: Dept. of Physiology, Monash University
• [Int'l Joint Research] Dept. of Physiology, Otago University(New Zealand)
  • Country Name: New Zealand
  • Counterpart Institution: Dept. of Physiology, Otago University
• [Journal Article] Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β3AR/iNOS pathway in rats exposed to chronic intermittent hypoxia. (2015)
  • Author(s): Nagai H, Kuwahira I, Schwenke DO, Tsuchimochi H, Nara A, Ogura S, Sonobe T, Inagaki T, Fujii Y, Yamaguchi R, Wingenfeld L, Umetani K, Shimosawa T, Yoshida K, Uemura K, Pearson JT, Shirai M.
  • Journal Title: PLoS ONE Volume: 10(7) Pages: e0131923
  • DOI: 10.1371/journal.pone.0131923.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ghrelin supresses sympathetic hyper-excitation in acute heart failure in male rats - assessing centrally and peripherally mediated pathways (2015)
  • Author(s): Shirai M, Joe N, Tsuchimochi H, Sonobe T, Schwenke DO.
  • Journal Title: Endocrinology Volume: 156 Pages: 3309-3316
  • DOI: 10.1210/EN.2015-1333.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Guanfacine enhances cardiac acetylcholine release with little effect on norepinephrine release in anesthetized rabbits. (2015)
  • Author(s): Shimizu S, Kawada T, Akiyama T, Turner MJ, Shishido T, Kamiya A, Shirai M, Sugimachi M.
  • Journal Title: Auton Neurosci Volume: 187 Pages: 84-87
  • DOI: 10.1016/j.autneu.2014.11.010.
  • Peer Reviewed
• [Journal Article] readmill running improves hindlimb arteriolar endothelial function in type 1 diabetic mice as visualized by X-ray microangiography. (2015)
  • Author(s): Sonobe T, Tsuchimochi H, Schwenke DO, Pearson JT, Shirai M.
  • Journal Title: Cardiovasc Diabetol Volume: 13 Pages: 14::51
  • DOI: 10.1186/s12933-015-0217-0.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. (2015)
  • Author(s): Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masakia T, Minami M, Inagaki T, Miyagawa S, Sawa Y, Murakami M, Kumanogoh A, Yamauchi-Takihara K, Okumura M, Kishimoto T, Komuro I, Shirai M, Sakata, Y, Nakaoka Y.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Pages: E2667-E2686
  • DOI: 10.1073/pnas.1424774112.
  • Peer Reviewed
• [Journal Article] APJ Regulates Parallel Alignment of Arteries and Veins in the Skin. (2015)
  • Author(s): Kidoya H, Naito H, Muramatsu F, Yamakawa D, Jia W, Ikawa M, Sonobe T, Tsuchimochi H, Shirai M, Adams RH, Fukamizu A, Takakura N.
  • Journal Title: Dev Cell Volume: 33 Pages: 247-259
  • DOI: 10.1016/j.devcel.2015.02.024.
  • Peer Reviewed
• [Journal Article] Chronic Rho-kinase inhibition improves left ventricular contractile dysfunction in early type-1 diabetes by increasing myosin cross-bridge extension. (2015)
  • Author(s): Waddingham MT, Edgley AJ, Astolfo A, Inagaki T, Fujii Y, Du CK, Zhan DY, Tsuchimochi H, Yagi N, Kelly DJ, Shirai M, Pearson JT.
  • Journal Title: Cardiovasc Diabetol Volume: 22 Pages: 14:92
  • DOI: 10.1186/s12933-015-0256-6.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Exercise training attenuates the development of diabetic cardiomyopathy through modulating inflammation and oxidative stress (2016)
  • Author(s): Sukumaran V, Inagaki T, Tsuchimochi H, Shirai M.
  • Organizer: The 93rd Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Sapporo
  • Year and Date: 2016-03-24 – 2016-03-24
  • Int'l Joint Research
• [Presentation] Sympathetic hyper-excitation in obesity and pulmonary hypertension; relevance to the Obesity Paradox (2016)
  • Author(s): Schwenke D, Diong C, Shirai M.
  • Organizer: The 93rd Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Sapporo
  • Year and Date: 2016-03-23 – 2016-03-23
  • Int'l Joint Research
• [Presentation] Chronic intermittent hypoxia accelerates coronary microcirculatory dysfunction in young insulin resistant Goto-Kakizaki rats. (2016)
  • Author(s): Perason J, Chen Y, Inagaki T, Fujii, Y, Schwenke D, Edgley A, Umetani K, Zhan Y, Yoshimoto M, Tsuchimochi H, Nagai H, Kuwahira I, Evans R, Shirai M.
  • Organizer: The 93rd Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Sapporo
  • Year and Date: 2016-03-22 – 2016-03-22
  • Int'l Joint Research
• [Presentation] Fluorescence imaging guided identification of autonomic nerve fibers and the measurement of their activities in vivo by using Thy1-YFP transgenic mice. (2016)
  • Author(s): Tsuchimochi H, Inagaki T, Shirai M.
  • Organizer: The 93rd Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: Sapporo
  • Year and Date: 2016-03-22 – 2016-03-22
• [Presentation] Critical protective role of endogenous nitric oxide in established severe pulmonary arterial hypertension in rats. (2015)
  • Author(s): Tanaka M, Abe K, Oka M, Schwenke DO, Shirai M, Kuwahira I, Hirooka Y, Hoka S, Sunagawa K.
  • Organizer: American Heart Association scientific session
  • Place of Presentation: Florida
  • Year and Date: 2015-11-10 – 2015-11-10
  • Int'l Joint Research
• [Presentation] The effect of blood contact surface area reduction during extracorporeal circulation in a rat cardiopulmonary bypass model. (2015)
  • Author(s): Fujii Y, Shirai M, Takewa Y, Taenaka Y, Tatsumi E
  • Organizer: American Society for Artificial Internal Organs 61th Annual Conference
  • Place of Presentation: Chicago
  • Year and Date: 2015-06-25 – 2015-06-25
  • Int'l Joint Research