Quantitative analysis of the open-state affinity of L-type calcium channel blockers and modeling of their inhibitory actions

2011 Fiscal Year Final Research Report

• Project/Area Number: 21590275
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Shinshu University
• Principal Investigator: YAMADA Mitsuhiko 信州大学, 医学部, 教授 (10263237)
• Co-Investigator(Renkei-kenkyūsha): NAKADA Tsutomu 信州大学, 医学部, 助教 (70452141)
• Project Period (FY): 2009 – 2011
• Keywords: Ca_V<1. 2> L型カルシウムチャネル / ジヒドロピリジン / 膜電位依存性不活性化 / Timothy症候群 / アロステリックモデル

Research Abstract

We found that an antihypertensive agent, nifedipine can prevent fatal ventricular arrhythmias. Nifedipine exerts its effect by blocking L-type Ca^<2+> channels, which mediate Ca^<2+> influx into cells. In this study, we introduced genes encoding the channels into cultured cells and analyzed their function, thereby identified the mechanism by which nifedipine causes the effect to prevent fatal ventricular arrhythmias.

Research Products

• [Journal Article] Two mechanistically distinct effects of dihydro pyridine nifedipine on Ca^V〈1. 2〉L-type Ca^<2+> channels revealed by Timothy syndrome mutation (2012)
  • Author(s): Sheng, X., Nakada, T., Kobayashi, M., Kashihara, T., Shibazaki, T., Horiuchi-Hirose, M., Gomi, S., Hirose, M., Aoyama, T., Yamada, M
  • Journal Title: Eur. J. Pharmacol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Chronic receptor-mediated activation of Gi/o proteins alters basal t-tubular and sarcolemmal L-type Ca^<2+> channel activity through phosphatases in heart failure (2012)
  • Author(s): Kashihara, T., Nakada, T., Shimojo, H., Horiuchi-Hirose, M., Gomi, S., Shibazaki, T., Sheng, X., Hirose, M., Hongo, M., and Yamada, M
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol Volume: 302 Pages: 1645-1654
  • DOI: DOI:10.1152/ajpheart.00589.2011
  • Peer Reviewed
• [Journal Article] Acid-sensing ion channels in blood volume regulation (2011)
  • Author(s): Yamada, M
  • Journal Title: Circ. J Volume: 75(4) Pages: 781-782
  • DOI: DOI:10.1253/circj.CJ-11-0085
  • Peer Reviewed
• [Journal Article] Diacylglycerol kinaseζInhibits ventricular tachyarrhythmias in a mouse model of heart failure (2011)
  • Author(s): Hirose, M., Takeishi, Y., Niizeki, T., Nakada, T., Shimojo, H., Kashihara, T., Horiuchi-Hirose, M., Kubota, I., Mende, U., Yamada, M
  • Journal Title: Role of canonical transient receptor potential(TRPC) channels-Circ J Volume: 75(10) Pages: 2333-2342
  • DOI: DOI:10.1253/circj.CJ-10-1213
  • Peer Reviewed
• [Journal Article] Decrease in the density of t-tubular L-type Ca^<2+> channel currents in failing ventricular my cytes (2011)
  • Author(s): Horiuchi-Hirose, M., Kashihara, T., Nakada, T., Kurebayashi, N., Shimojo, H., Shibazaki, T., Sheng, X., Yano, S., Hirose, M., Hongo, M., Sakurai, T., Moriizumi, T., Ueda, H., and Yamada, M
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol Volume: 300(3) Pages: 978-988
  • DOI: DOI:10.1152/ajpheart.00508.2010
  • Peer Reviewed
• [Journal Article] Thrombin activates Ca^<2+>-permeating nonselective cation channels through protein kinase C in human umbilical vein endothelial cells (2011)
  • Author(s): Tsujino, N, Nakada, T., Tsubouchi, K., Kobayashi, M., Kawai, Y., Yano, S., Matsunaga, T., Hirose, M., Ohmori, S., Ohhashi, T., Yamada, M
  • Journal Title: Shinshu Med. J Volume: 59 Pages: 13-26
  • Peer Reviewed
• [Journal Article] Nicorandil ameliorates impulseconduction disturbances during ischemia in isolated arterially perfused canine atria (2011)
  • Author(s): Hirose, M., Yano, S., Nakada, T., Horiuchi-irose, M., Tsujino, N., Yamada, M
  • Journal Title: Int. J. Cardiol Volume: 146 Pages: 37-43
  • DOI: 10.1016/j.ijcard.2009.06.011
  • Peer Reviewed
• [Journal Article] Mitochondrial ATP-sensitive K^+ channels, protectors of the heart (2010)
  • Author(s): Yamada, M
  • Journal Title: J. Physiol.(Lond) Volume: 582 Pages: 283-286
  • DOI: DOI:10.1113/jphysiol.2009.179028
  • Peer Reviewed
• [Journal Article] Selectiveα_〈1A〉-adrenoceptor stimulation induces Mueller' s smooth muscle contraction in an isolated canine upper eyelid preparation (2010)
  • Author(s): Yano, S., Hirose, M., Nakada, T., Nakayama, J., Matsuo, K., Yamada, M
  • Journal Title: Curr. Eye Res Volume: 35 Pages: 363-369
  • DOI: DOI:10.3109/02713680903518858
  • Peer Reviewed
• [Journal Article] Effects of hormone-sensitive lipase-disruption on cardiac energy metabolism in response to fasting and refeeding (2009)
  • Author(s): Suzuki, J., Ueno, M., Uno, M., Hirose, Y., Zenimaru, Y., Takahashi, S., Osuga, J. I., Ishibashi, S., Takahashi, M., Hirose, M., Yamaa, M., Kraemer, F. B., Miyamori, I
  • Journal Title: Am. J. Physiol. Endocrinol. Metab Volume: 297 Pages: 1115-1124
  • DOI: DOI:10.1152/ajpendo.91031.200
  • Peer Reviewed
• [Journal Article] Diaclglycerol seζinhibits G_〈αq〉-induced atrial remodeling in transgenic mice (2009)
  • Author(s): Hirose, M., Takeishi, Y., Niizeki, T., Shimojo, H., Nakada, T., Kubota, I., Nakayama J., Mende, U., Yamada, M
  • Journal Title: Heart Rhythm Volume: 6 Pages: 78-84
  • DOI: 10.1016/j.hrthm.200810.018
  • Peer Reviewed
• [Presentation] I_<Kr>and I_<Kr>channel suppressn cses early after depolarizations by preventing deactivation L-type Ca^<2+> channs in ventricular myocytes (2009)
  • Author(s): Yamada, M., Ohta, K., Niwa, A., Tsujino, N., akada, T. and Hirose, M
  • Organizer: The 36th International Congress of Physiological Sciences
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20090727-0801
• [Book] 心筋細胞とメカニカルストレス応答 (2009)
  • Author(s): 山田充彦、南山堂横山光宏、井上信孝
  • Total Pages: 91-99
  • Publisher: 循環器ストレス学
• [Remarks] 大学公式ホームページ
  • URL: http://www.shinshu-u.ac.jp/graduate/medicine/doctoral/m-science/yakuri.html