Basic research for exploitation of novel central antihypertensive drugs focusing on regulation of responses to stress

• Project/Area Number: 26460909
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Kochi University
• Principal Investigator: SHIMIZU Takahiro 高知大学, 教育研究部医療学系基礎医学部門, 准教授 (00363276)
• Co-Investigator(Kenkyū-buntansha): 清水 翔吾 高知大学, 教育研究部医療学系基礎医学部門, 助教 (90721853) ; 中村 久美子 高知大学, 教育研究部医療学系基礎医学部門, 技術専門職員 (30398052) ; 田中 健二朗 高知大学, 教育研究部医療学系基礎医学部門, 助教 (30552260) ; 八幡 俊男 高知大学, 教育研究部医療学系臨床医学部門, 助教 (40380323) ; 東 洋一郎 高知大学, 教育研究部医療学系基礎医学部門, 助教 (80380062)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 脳内大麻 / エンドカンナビノイド / CB受容体 / 自然発症高血圧ラット / 高血圧症 / 交感神経-副腎髄質系 / 脳内麻薬 / オピオイド受容体 / 中枢性交感神経―副腎髄質系 / オピオイド / μ受容体

Outline of Final Research Achievements

The sympatho-adrenomedullary (SA) system is an important component of responses to stress, and it has recognized that excessive activation of this system plays a pathogenic role in triggering and sustaining the essential hypertension. We have already reported an inhibitory role of brain endocannabinoid (eCB) in stress-related neuropeptides-induced activation of the SA outflow via brain CB1 receptors. In this study, we clarified that (1) stimulation of brain CB1 receptors improved excessive hypertension and activation of the outflow in spontaneously hypertensive rats without affecting these factors in normotensive control rats, and that (2) brain opioid receptors, which can interact with CB1 receptors, modulate these peptides-induced activation of the SA outflow. These findings suggest that brain CB1 and opioid receptors might be useful targets for alleviation of essential hypertension via inhibition of stress responses including the SA outflow.

Research Products

• [Journal Article] PHARMACOLOGICAL CHARACTERIZATION OF BRAIN SEROTONIN RECEPTOR SUBTYPES INVOLVED IN BOMBESIN-INDUCED FREQUENT URINATION IN RATS (2016)
  • Author(s): Shimizu T, Shimizu S, Wada N, Takai S, Shimizu N, Higashi Y, Kadekawa K, Majima T, Saito M, Yoshimura N.
  • Journal Title: Neurourol Urodyn Volume: 35
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of naftopidil on brain noradrenaline-induced decrease in arginine-vasopressin secretion in rats (2016)
  • Author(s): Yamamoto M, Shimizu T, Shimizu S, Higashi Y, Nakamura K, Fujieda M, Saito M
  • Journal Title: J Pharmacol Sci Volume: 132 Issue: 1 Pages: 86-91
  • DOI: 10.1016/j.jphs.2016.09.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brain opioid and nociceptin receptors are involved in regulation of bombesin-induced activation of central sympatho-adrenomedullary outflow in the rat. (2016)
  • Author(s): Yawata T, Higashi Y, Shimizu T, Shimizu S, Nakamura K, Taniuchi K, Ueba T, Saito M.
  • Journal Title: Mol. Cell. Biochem. Volume: 411 Issue: 1-2 Pages: 201-211
  • DOI: 10.1007/s11010-015-2582-0
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A stress-related peptide bombesin centrally induces frequent urination through brain bombesin receptor types 1 and 2 in the rat. (2016)
  • Author(s): Shimizu T, Shimizu S, Higashi Y, Nakamura K, Yoshimura N, Saito M.
  • Journal Title: J. Pharmacol. Exp. Ther. Volume: 356 Issue: 3 Pages: 693-701
  • DOI: 10.1124/jpet.115.230334
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Angiotensin II centrally induces frequent urination by acting on brain angiotensin II type 1 receptors in rats. (2016)
  • Author(s): Kawamoto B, Shimizu S, Shimizu T, Higashi Y, Honda M, Sejima T, Saito M, Takenaka A.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 22213-22213
  • DOI: 10.1038/srep22213
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible inhibitory role of endogenous 2-arachidonoylglycerol as an endocannabinoid in (±)-epibatidine-induced activation of central adrenomedullary outflow in the rat. (2015)
  • Author(s): Shimizu T, Tanaka K, Shimizu S, Higashi Y, Yawata T, Nakamura K, Taniuchi K, Ueba T, Yuri K, Saito M
  • Journal Title: Neuropharmacology Volume: 95 Pages: 278-289
  • DOI: 10.1016/j.neuropharm.2015.03.034
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] BOMBESIN, A STRESS-RELATED NEUROPEPTIDE, CENTRALLY INDUCES FREQUENT URINATION IN THE RAT (2015)
  • Author(s): Shimizu T, Shimizu S, Higashi Y, Nakamura K, Kadekawa K, Wada N, Majima T, Honda M, Yoshimura N, Saito M
  • Journal Title: Neurourol. Urodyn. Volume: 34
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ヘモグロビン由来ペプチド・ヘモプレッシンによる交感神経―副腎髄質系賦活に対する中枢性制御 (2015)
  • Author(s): 清水孝洋、齊藤源顕
  • Journal Title: The Autonomic Nervous System (Journal of the Japan Society of Neurovegetative Research) Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Angiotensin II acting on brain AT1 receptors induces adrenaline secretion and pressor responses in the rat. (2014)
  • Author(s): Nakamura K, Shimizu T, Yanagita T, Nemoto T, Taniuchi K, Shimizu S, Dimitriadis F, Yawata T, Higashi Y, Ueba T, Saito, M
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 7248-7248
  • DOI: 10.1038/srep07248
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] ストレス関連ペプチドのボンベシンにより中枢性に誘発される頻尿には脳内セロトニン神経系が関与する (2017)
  • Author(s): 清水孝洋、清水翔吾、和田直樹、高井峻、清水信貴、東洋一郎、嘉手川豪心、馬嶋剛、吉村直樹、齊藤源顕
  • Organizer: 日本薬学会第１３７年会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2017-03-24
• [Presentation] ストレス関連ペプチドのボンベシンは脳内セロトニン神経系を介して頻尿を惹起する (2017)
  • Author(s): 清水孝洋、清水翔吾、和田直樹、高井峻、清水信貴、東洋一郎、嘉手川豪心、馬嶋剛、吉村直樹、齊藤源顕
  • Organizer: 第９０回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール、長崎新聞文化ホール アストピア（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] 中枢性ノルアドレナリン投与ラットにおけるアルギニンーバソプレッシン分泌減少はα1アドレナリン受容体遮断薬ナフトピジルにより抑制される (2017)
  • Author(s): 中村久美子、清水孝洋、清水翔吾、東洋一郎、山本雅樹、劉南希、新武享朗、長尾佳樹、齊藤源顕
  • Organizer: 第９０回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール、長崎新聞文化ホール アストピア（長崎県長崎市）
  • Year and Date: 2017-03-15
• [Presentation] ストレス関連ペプチドのボンベシンにより中枢性に誘発される頻尿に関与する脳内セロトニン受容体サブタイプの同定 (2016)
  • Author(s): 清水孝洋、清水翔吾、和田直樹、高井峻、清水信貴、東洋一郎、嘉手川豪心、馬嶋剛、齊藤源顕、吉村直樹
  • Organizer: 第２３回日本排尿機能学会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-12-06
• [Presentation] ノルアドレナリン脳室内投与ラットにおける血中アルギニンバソプレッシン量及び尿量に対するα1受容体遮断薬ナフトピジルの効果 (2016)
  • Author(s): 清水翔吾、清水孝洋、山本雅樹、東洋一郎、中村久美子、劉南希、本田正史、齊藤源顕
  • Organizer: 第２３回日本排尿機能学会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-12-06
• [Presentation] ストレス関連ペプチドのボンベシンによる頻尿誘発には脳内セロトニン受容体が関与する (2016)
  • Author(s): 清水孝洋、清水翔吾、和田直樹、高井峻、清水信貴、東洋一郎、嘉手川豪心、馬嶋剛、吉村直樹、齊藤源顕
  • Organizer: 第１回黒潮カンファレンス
  • Place of Presentation: サンライズ九十九里（千葉県山武郡九十九里町）
  • Year and Date: 2016-10-22
• [Presentation] PHARMACOLOGICAL CHARACTERIZATION OF BRAIN SEROTONIN RECEPTOR SUBTYPES INVOLVED IN BOMBESIN-INDUCED FREQUENT URINATION IN RATS (2016)
  • Author(s): Shimizu T, Shimizu S, Wada N, Takai S, Shimizu N, Higashi Y, Kadekawa K, Majima T, Saito M, Yoshimura N
  • Organizer: International Continence Society (ICS) 2016
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] EFFECT OF ALPHA1 ADRENOCEPTOR ANTAGONIST NAFTOPIDIL ON THE ARGININE-VASOPRESSIN SECRETION AND URINE VOLUME IN CENTRALLY NORADRENALINE-ADMINISTERED RATS (2016)
  • Author(s): Shimizu S, Shimizu T, Yamamoto M, Higashi Y, Nakamura K, Tsounapi P, Liu N, Honda M, Takenaka A, Saito M
  • Organizer: International Continence Society (ICS) 2016
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-09-13
  • Int'l Joint Research
• [Presentation] Brain serotonin and corticotropin-releasing factor are involved in bombesin-induced frequent urination in rats (2016)
  • Author(s): Shimizu T, Shimizu S, Wada N, Takai S, Shimizu N, Kadekawa K, Majima T, Higashi Y, Saito M, Yoshimura N
  • Organizer: American Urological Association, 111th Annual Meeting
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] Effect of naftopidil on the brain noradrenaline-induced decrease of arginine-vasopressin secretion in rats (2016)
  • Author(s): Shimizu T, Shimizu S, Higashi Y, Yamamoto M, Nakamura K, Yoshimura N, Saito M
  • Organizer: American Urological Association, 111th Annual Meeting
  • Place of Presentation: San Diego (USA)
  • Year and Date: 2016-05-06
  • Int'l Joint Research
• [Presentation] 脳室内アンジオテンシンIIの中枢性AT1受容体を介した排尿反射への影響 (2016)
  • Author(s): 川本文弥, 清水翔吾, 清水孝洋, 東洋一郎, 中村久美子, 引田克弥, 村岡邦康, 本田正史, 瀬島健裕, 齊藤源顕, 武中篤
  • Organizer: 第１０４回日本泌尿器科学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-04-23
• [Presentation] Central angiotensin II induces frequent urination through brain angiotensin II receptor type 1 in the rat. (2016)
  • Author(s): Shogo Shimizu, Bunya Kawamoto, Takahiro Shimizu, Youichirou Higashi, Kumiko Nakamura, Takaaki Aratake, Masaki Yamamoto, Motoaki Saito.
  • Organizer: 第８９回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜会議センター（神奈川県横浜市）
  • Year and Date: 2016-03-09
• [Presentation] ストレス関連ペプチドのボンベシンは脳内セロトニン神経系を介して中枢性に頻尿を誘発する (2016)
  • Author(s): 清水孝洋、清水翔吾、和田直樹、高井峻、清水信貴、東洋一郎、嘉手川豪心、馬嶋剛、吉村直樹、齊藤源顕
  • Organizer: 第６９回日本薬理学会西南部会
  • Place of Presentation: 松山大学（愛媛県松山市）
• [Presentation] ノルアドレナリン脳室内投与ラットにおける、血中バソプレッシン量、尿量及び尿上清浸透圧に対するナフトピジルの効果 (2016)
  • Author(s): 中村久美子、清水孝洋、清水翔吾、山本雅樹、東洋一郎、劉南希、新武享朗、齊藤源顕
  • Organizer: 第６９回日本薬理学会西南部会
  • Place of Presentation: 松山大学（愛媛県松山市）
• [Presentation] 脳内アンジオテンシンIIは中枢性AT1受容体を介して排尿反射を惹起する (2015)
  • Author(s): 清水翔吾、川本文弥、清水孝洋、東洋一郎、中村久美子、新武享朗、齊藤源顕
  • Organizer: 第６８回日本薬理学会西南部会
  • Place of Presentation: 海峡メッセ下関（山口県下関市）
  • Year and Date: 2015-11-21
• [Presentation] Central Angiotensin II Induces Frequent Urination in Rats. (2015)
  • Author(s): Bunya Kawamoto, Shogo Shimizu, Takahiro Shimizu, Youichirou Higashi, Katsuya Hikita, Kuniyasu Muraoka, Masashi Honda, Takehiro Sejima, Motoaki Saito, Atsushi Takenaka
  • Organizer: 第６７回西日本泌尿器科学会総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-05
• [Presentation] BOMBESIN, A STRESS-RELATED NEUROPEPTIDE, CENTRALLY INDUCES FREQUENT URINATION IN THE RAT. (2015)
  • Author(s): Shimizu T, Shimizu S, Higashi Y, Nakamura K, Kadekawa K, Wada N, Majima T, Honda M, Yoshimura N, Saito M.
  • Organizer: International Continence Society (ICS) 2015
  • Place of Presentation: Montreal (Canada)
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] Central angiotensin II increases urinary frequency by acting on brain AT1 receptors in rats. (2015)
  • Author(s): Kawamoto B, Shimizu S, Hikita K, Muraoka K, Honda M, Sejima T, Higashi Y, Shimizu T, Saito M, Takenaka A.
  • Organizer: International Continence Society (ICS) 2015
  • Place of Presentation: Montreal (Canada)
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] 中枢性アンジオテンシンIIが排尿反射に及ぼす影響 (2015)
  • Author(s): 川本文弥、清水翔吾、清水孝洋、東洋一郎、引田克弥、村岡邦康、本田正史、瀬島健裕、武中篤、齊藤源顕
  • Organizer: 第８０回日本泌尿器科学会東部総会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-09-25
• [Presentation] ストレス関連ペプチドのボンベシンは中枢性に頻尿を誘発する (2015)
  • Author(s): 清水孝洋、清水翔吾、齊藤源顕
  • Organizer: 第２２回日本排尿機能学会
  • Place of Presentation: 京王プラザホテル札幌（北海道札幌市）
  • Year and Date: 2015-09-09
• [Presentation] 脳室内アンギオテンシンⅡは中枢性AT1受容体を介して頻尿を惹起する (2015)
  • Author(s): 川本文弥、清水翔吾、清水孝洋、東洋一郎、引田克弥、村岡邦康、本田正史、瀬島健裕、武中篤、齊藤源顕
  • Organizer: 第２２回日本排尿機能学会
  • Place of Presentation: 京王プラザホテル札幌（北海道札幌市）
  • Year and Date: 2015-09-09
• [Presentation] Bombesin centrally induces frequent urination in the rat. (2015)
  • Author(s): Kumiko Nakamura, Takahiro Shimizu, Shogo Shimizu, Felix Holmström, Youichirou Higashi, Toshio Yawata, Motoaki Saito.
  • Organizer: 第８８回日本薬理学会年会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-03-18 – 2015-03-20
• [Presentation] 脳室内投与アンジオテンシンⅡは、中枢性にAT1受容体を介して副腎髄質からアドレナリンを遊離させる (2014)
  • Author(s): 中村久美子、清水孝洋、柳田俊彦、根本隆行、清水翔吾、谷内恵介、東洋一郎、Holmstrom Felix、齊藤源顕
  • Organizer: 第６７回日本薬理学会西南部会
  • Place of Presentation: 産業医科大学（福岡県北九州市）
  • Year and Date: 2014-11-23
• [Remarks] 高知大学医学部薬理学講座
  • URL: http://www.kochi-ms.ac.jp/~ff_phrmc/
• [Remarks] 高知大学医学部薬理学講座
  • URL: http://www.kochi-ms.ac.jp/~ff_phrmc/index.html