Studies on the role of Ttype calcium channels in the cardiovascular system using a specific inhibitor

• Project/Area Number: 18590243
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Toho University
• Principal Investigator: TANAKA Hikaru Toho University, Faculty of Pharmaceutical Sciences, Professor (40236617)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: T-type calcium channel / dihvelrnnvricline / heart rate / action notential / sinoatrial node / エホニジピン / 心収縮力 / 幼若期 / 心臓 / 自動能

Research Abstract

The T-type calcium channel has different properties and distribution for those of the L-type. It is considered to be involved in various physiological and pathophysiological phenomena such as cardiac automaticity, secretion of various active substances, and is therefore anticipated to be a novel therapeutic target. In the this project, I studied the physiological role of the T-type calcium channel using R (-) -efonidipine, the specific inhibitor I found in my previous studies. Contractile force experiments with isolated murine ventricular tissue revealed that the T-type calcium channel contributes to myocardial contraction in the fetal period but not at adulthood. Activation of the T-type calcium channel was involved in the endothelin- 1-induced positive inotropy. Microelectrode recordings in isolated sinoatrial-node preparations revealed that the T-type calcium channel is involved in the pacemaker depolarization of the mouse and guinea-pig but not in the rabbit, which agreed with earliler data on current density. This indicated that the different contribution of the T-type calcium current to pacemaking underlies species difference in heart rate. As it was shown that the factors which determines heart rate is different among species and the condition of the heart, extension of the present study to hearts from various pathological models may lead to the development of novel pharmacological therapy through regulation of heart rate.

Research Products

• [Journal Article] Species difference in the contribution of T-type calcium current to cardiac pacemaking as revealed by R(-)-efonidipine (2008)
  • Author(s): Hikaru TANAKA, et. al.
  • Journal Title: J.Pharmacol.Sci. 107 Pages: 99-102
  • NAID: 10024320633
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Membrane-labelled MDCK cells and confocal microscopy for the analyses of cellular volume and morphology (2008)
  • Author(s): Naoko IIDA-TANAKA, Hikaru TANAKA, et. al.
  • Journal Title: Biol.Pharm.Bull. 34 Pages: 731-734
  • NAID: 110006680516
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intracellular mechanisms and receptor types for endothelia-1-induced positive and negative inotropy in mouse ventricular myocardium (2008)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Journal Title: Naunyn-Schmied.Arch.Pharmacol. 376 Pages: 386-395
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Species difference in the contribution of T-type calcium current to cardiac pacemaking as revealed by R(-)-efonidipine (2008)
  • Author(s): Tanaka, H., Komikado, C., Namekata, I., Nakamura, H., Suzuki, M., Tsuneoka, Y., Shigenobu, K., Takahara, A
  • Journal Title: J. Pharmacol. Sci 107 Pages: 99-102
  • NAID: 10024320633
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Membrane-labelled MDCK cells and confocal microscopy for the analyses of cellular volume and morphology (2008)
  • Author(s): Iida-Tanaka, N., Namekata, I., Tamura, M., Kawamata, Y., Kawanishi, T., Tanaka, H
  • Journal Title: Biol. Pharmaceut. Bull 34 Pages: 731-734
  • NAID: 110006680516
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intracellular mechanisms and receptor types for endothelin- 1-induced positive and negative inotropy in mouse ventricular myocardium. (2008)
  • Author(s): Namekata, I., Fujiki, S., Kawakami, Y., Moriwaki, R., Takeda, K., Kawanishi, T., Takahara, A., Shigenobu, K., Tanaka, H
  • Journal Title: Naunyn Schmied Arch. Pharmacol 376 Pages: 386-395
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Species difference in the contribution of T-type calcium current to cardiac pacemaking as revealed by R(-)-efonidipine. (2008)
  • Author(s): Hikaru TANAKA, et. al.
  • Journal Title: J. Pharmacol. Sci. (in press)
  • NAID: 10024320633
  • Peer Reviewed
• [Journal Article] Membrane-labelled MDCK cells and confocal microscopy for the analyses of cellular volume and morphology. (2008)
  • Author(s): Naoko IIDA-TANAKA, Hikaru TANAKA, et. al.
  • Journal Title: Biol. Pharm. Bull. 34 Pages: 731-734
  • NAID: 110006680516
  • Peer Reviewed
• [Journal Article] Intracellular mechanisms and receptor types for endothelin-1-induced positive and negative inotropy in mouse ventricular myocardium. (2008)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Journal Title: Naunyn-Schmied. Arch. Pharmacol. 376 Pages: 386-395
  • Peer Reviewed
• [Journal Article] (R)-ACX,a pancreatic beta-cell selective sulfonylurea,does not aggravate myocardial ischemia-reperfusion damage (2007)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Journal Title: Eur.J.Pharmacol. 577 Pages: 211-218
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of intracellular Ca^<2+> in the regulatory volume decrease after hyposmotic swelling in MDCK cells (2007)
  • Author(s): Naoko IIDA-TANAKA, Hikaru TANAKA, et. al.
  • Journal Title: J.Pharmacol.Sci. 104 Pages: 397-401
  • NAID: 10024315429
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Endocardial endothelium-dependent positive inotropy by Ca^<2+> pump inhibitors:posible involvement of store-operated Ca^<2+> entry (2007)
  • Author(s): Kazuhide NISHIMARU, Hikaru TANAKA, et. al.
  • Journal Title: Pharmacology 80 Pages: 200-206
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class III antiarrhythmic drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart (2007)
  • Author(s): Akira TAKAHARA, Hikaru TANAKA, et. al.
  • Journal Title: J.Pharmacol.Sci. 103 Pages: 181-18
  • NAID: 10024312542
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Involvement of the Na^+/Ca^<2+> exchanger in ouabain-induced inotropy and arrhythmogenesis in guinea-pig myocardium as revealed by SEA0400 (2007)
  • Author(s): Hikaru TANAKA, et. al.
  • Journal Title: J.Pharmacol.Sci. 103 Pages: 241-246
  • NAID: 10024312778
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] (R)-ACX, a pancreatic b-cell selective sulfonylurea, does not aggravate myocardial ischemia-reperfusion damage (2007)
  • Author(s): Namekata, I., Yamaguchi, Y., Moriguchi, S., Yamazaki, S., Terasawa, A., Yamagishi, R., Aikawa, T., Saito, T., Kurashima, K., Seri, K., Imamura, Y., Akita, H., Shigenobu, K., Tanaka. H
  • Journal Title: Eur. J. Pharmacol 577 Pages: 211-218
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of intracellular Ca^<2+> in the regulatory volume decrease after hyposmotic swelling in MDCK cells (2007)
  • Author(s): Iida-Tanaka, N., Namekata, I., Kaneko, M., Tamura, M., Kawanishi, T., Nakamura, R., Shigenobu, K., Tanaka, H
  • Journal Title: J. Pharmacol. Sci 104 Pages: 397-401
  • NAID: 10024315429
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Endocardial endothelium-dependent positive inotropy by Ca<2+> pump inhibitors : possible involvement of store-operated Ca<2+> entry. (2007)
  • Author(s): Nishimaru, K., Fujiki, S., Tanaka, Y., Tanaka, H., Shigenobu, K
  • Journal Title: Pharmacology 80 Pages: 200-206
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class III antiarrhythmic drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart (2007)
  • Author(s): Takahara, A., Nakamura, H., Nouchi, H., Tamura, T., Tanaka, T., Shimada, H., Tamura, M., Tsuruoka, N., Takeda, K., Tanaka, H., Shigenobu, K., Hashimoto, K., Sugiyama, A
  • Journal Title: J. Pharmacol. Sci 103 Pages: 181-188
  • NAID: 10024312542
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of the Na^+/Ca^+ exchanger in ouabaininduced inotropy and arrhythmogenesis in guinea-pig myocardium as revealed by SEAO400 (2007)
  • Author(s): Tanaka, H., Shimada, H., Namekata, I., Kawanishi, T., lida-Tanaka, N., Shigenobu, K
  • Journal Title: J. Pharmacol. Sci 103 Pages: 241-246
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (R)-ACX, a pancreatic beta-cell selective sulfonylurea, does not aggravate myocardial ischemia-reperfusion damage. (2007)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Journal Title: Eur. J. Pharmacol. 577 Pages: 211-218
  • Peer Reviewed
• [Journal Article] Involvement of intracellular Ca^<2+> in the regulatory volume decrease after hyposmotic swelling in MDCK cells. (2007)
  • Author(s): Naoko IIDA-TANAKA, Hikaru TANAKA, et. al.
  • Journal Title: J. Pharmacol. Sci. 104 Pages: 397-401
  • NAID: 10024315429
  • Peer Reviewed
• [Journal Article] Endocardial endothelium-dependent positive inotropy by Ca^<2+> pump inhibitors: possible involvement of store-operated Ca^<2+> entry. (2007)
  • Author(s): Kazuhide NISHIMARU, Hikaru TANAKA, et. al.
  • Journal Title: Pharmacology 80 Pages: 200-206
  • Peer Reviewed
• [Journal Article] Analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class III antiarrhythmic drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart. (2007)
  • Author(s): Akira TAKAHARA, Hikaru TANAKA, et. al.
  • Journal Title: J. Pharmacol. Sci. 103 Pages: 181-188
  • NAID: 10024312542
  • Peer Reviewed
• [Journal Article] Involvement of the Na^+/Ca^<2+> exchanger in ouabain-induced inotropy and arrhythmogenesis in guinea-pig myocardium as revealed by SEA0400. (2007)
  • Author(s): Hikaru TANAKA, et. al.
  • Journal Title: J. Pharmacol. Sci. 103 Pages: 241-246
  • NAID: 10024312778
  • Peer Reviewed
• [Journal Article] Enhancement of methoxamine-induced contractile responses of rat ventricle in streptozotocin-induced diabetes is associated with α1Aadrenoceptor upregulation (2006)
  • Author(s): Katsuo KAMAKA, Hikaru TANAKA, et. al.
  • Journal Title: Acta.Physiol.Scand. 188 Pages: 173-183
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Blockade by NIP-142 of carbachol-induced action potential shortening and GIRK 1/4 channel (2006)
  • Author(s): Tomoyuki MATSUDA, Hikaru TANAKA, et. al.
  • Journal Title: J.Pharmacol.Sci. 101 Pages: 303-310
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Quantitative fluorescence measurement of cardiac Na^+/Ca^<2+> exchanger inhibition by kinetic analysis in stably transfected HEK293 cells (2006)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Journal Title: J.Pharmacol.Sci. 101 Pages: 356-360
  • NAID: 10018236708
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca^<2+> overload (2006)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Journal Title: Eur.J.Pharmacol. 533 Pages: 108-115
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Enhancement of methoxamine-induced contractile responses of rat ventricle in streptozotocin-induced diabetes is associated with αlAadrenoceptor upregulation (2006)
  • Author(s): Kamata, K., Satoh, T., Matsumoto, T., Noguchi, E., Taguchi, K., Kobayashi, T., Tanaka, H., Shigenobu, K
  • Journal Title: Acta. Physiol. Scand 188 Pages: 173-183
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Blockade by NIP-142 of carbachol-induced action potential shortening and GIRK 1/4 channel (2006)
  • Author(s): Matsuda, T., Ito, M., Ishimaru, S., Tsuruoka, N., Saito, T., Iida-Tanaka, N., Hashimoto, N., Yamashita, T., Tsuruzoe, N., Tanaka, H., Shigenobu, K
  • Journal Title: J. Pharmacol. Sci 101 Pages: 303-310
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Quantitative fluorescence measurement of cardiac Na+/Ca2+ exchanger inhibition by kinetic analysis in stably transfected HEK293 cells (2006)
  • Author(s): Namekata, I., Kawanishi, T., Iida-Tanaka, N., Tanaka, H., Shigenobu, K
  • Journal Title: J. Pharmacol. Sci 101 Pages: 356-360
  • NAID: 10018236708
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca^<2+> overload (2006)
  • Author(s): Namekata, I., Shimada, H., Kawanishi, T., Tanaka, H., Shigenobu, K
  • Journal Title: Eur. J. Pharmacol 533 Pages: 108-115
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tanaka H., Shigenobu K. : Quantitative fluorescence measurement of cardiac Na^+/Ca^<2+> exchanger inhibition by kinetic analysis in stably transfected HEK293 cells. (2006)
  • Author(s): 行方衣由紀, 川西徹, 飯田田中直子, 田中光, 重信弘毅
  • Journal Title: J. Pharmacol. Sci. 101 Pages: 356-360
• [Journal Article] Reduction by SEA0400 of myocardial ischemia-induced cytoplasmic and mitochondrial Ca^<2+> overload. (2006)
  • Author(s): 行方衣由紀, 島田英朗, 川西徹, 田中光, 重信弘毅
  • Journal Title: Eur. J. Pharmacol. 533 Pages: 108-115
• [Journal Article] Blockade by NIP-142 of carbachol-induced action potential shortening and GIRK 1/4 channel. (2006)
  • Author(s): 松田智行, 伊藤美恵, 石丸小夜子, 鶴岡範子, 齋藤智亮, 橋本哲郎, 田中光, 重信弘毅
  • Journal Title: J. Pharmacol. Sci. 101 Pages: 303-310
• [Presentation] モルモット摘出肺静脈の活動電位に対するカリウムチャネル抑制薬の影響 (2008)
  • Author(s): 杉本貴彦
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-19
• [Presentation] 心筋の興奮収縮機構の多様性 (2008)
  • Author(s): 田中光
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] 洞房結節活動電位の緩徐脱分極相にα1Dチャネル電流が寄与する:S(+)-efonidipineを用いた検討 (2008)
  • Author(s): 小川亨
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] 低浸透圧負荷に対するMDCK細胞の減少性容積制御の細胞内Ca2+イオン依存性 (2008)
  • Author(s): 行方衣由紀
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] 発達に伴うニワトリ心室筋活動電位再分極相の変化 (2008)
  • Author(s): 野内秀明
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] L/T型カルシウム拮抗薬エホニジピンの反射性頻脈に対する抑制効果 (2008)
  • Author(s): 宇野洋司
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] SERCA活性化薬によるSTZ誘発性糖尿病マウス摘出心室筋のCa2+排出と弛緩機能の改善 (2008)
  • Author(s): 大原皆人
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-18
• [Presentation] T型Ca2+チャネルの心臓ペースメーカー活動への寄与は動物種で異なる (2007)
  • Author(s): 恒岡弥生
  • Organizer: 第1回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-12-15
• [Presentation] QT延長を誘発する薬剤の検出モデルとしてのニワトリ胚心筋の有用性 (2007)
  • Author(s): 木股幹雄
  • Organizer: 第1回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-12-15
• [Presentation] 鶏胚心筋を用いた薬物の催不整脈性評価法 (2007)
  • Author(s): 野内秀明
  • Organizer: 第117回日本薬理学会関東部会
  • Place of Presentation: 東京
  • Year and Date: 2007-10-06
• [Presentation] モルモット肺静脈の電気生理学的特性 (2007)
  • Author(s): 島田英朗
  • Organizer: 第24回日本心電学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-10-05
• [Presentation] Utility of the embryonic chick ventricle as a new model to QT-interval prolonging drugs. (2007)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Organizer: The 2007 Autumn Meeting of The British Society for Cardiovascular Research
  • Place of Presentation: London
  • Year and Date: 2007-09-09
• [Presentation] Embryonic chick myocardium as a sensitive model for prediction of drug-induced QT-interval prolongation (2007)
  • Author(s): Iyuki NAMEKATA, Hikaru TANAKA, et. al.
  • Organizer: The 2007 Autumn Meeting of The British Society for Cardiovascular Research
  • Place of Presentation: Edinburgh
  • Year and Date: 2007-09-07
• [Presentation] AQP3 confers resistance to osmotic stress in MDCK cells. (2007)
  • Author(s): Mai TAMURA, Hikaru TANAKA, et. al.
  • Organizer: The 5th International Conference of Aquaporin
  • Place of Presentation: Nara
  • Year and Date: 2007-07-15
• [Presentation] ミトコンドリアCa2+動態に対するSEA0400の影響 (2007)
  • Author(s): 行方衣由紀
  • Organizer: 第116回日本薬理学会関東部会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-02
• [Presentation] Effect of R(-)-efonidipine,a selective T-type Ca^<2+> channel blocker,on myocardial automaticity (2006)
  • Author(s): Chisa KOMIKADO, Hikaru TANAKA, et. al.
  • Organizer: The 23rd Annual Meeting of ISHR Japanese Section
  • Place of Presentation: 千葉
  • Year and Date: 2006-12-01
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Effect of R(-)-efonidipine, a selective T-type Ca^<2+> channel blocker, on myocardial automaticity (2006)
  • Author(s): Komikado, C., Shimada, H., Takeda, K., Namekata, I., Kawanishi, T., Tanaka, H., Shigenobu, K
  • Organizer: The 23rd Annual Meeting of ISHR Japanese Section
  • Place of Presentation: Chiba
  • Description: 「研究成果報告書概要(欧文)」より
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.mnc.toho-u.ac.jp/v-lab/shinkin/index.html
• [Remarks]
  • URL: http://www.mnc.toho-u.ac.jp/v-lab/shinkin/index.html