Innovation of treatment for malignant hyperthermia and arrhythmia by inhibition of abnormal intracellular Ca2+ release through the ryanodine receptor

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology/Resuscitation studies
• Research Institution: Yamaguchi University
• Principal Investigator: KOBAYASHI SHIGEKI 山口大学, 医学部附属病院, 講師 (90397993)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Takeshi 山口大学, 大学院医学系研究科, 准教授 (50363122) ; YANO Masafumi 山口大学, 大学院医学系研究科, 教授 (90294628)
• Project Period (FY): 2011 – 2013
• Keywords: 悪性高熱症 / 心室頻拍症 / 心不全 / ダントロレン / リアノジン受容体

Research Abstract

We previously reported that dantrolene, a therapeutic agent for malignant hyperthermia (MH), prevented abnormal Ca2+ leak by correction of the defective inter-domain interaction between N-terminal and central domains in MH-type RyR. In tachycardia-induced heart failure canine model and catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2R2474S /+ knock-in (KI) mice model, dantrolene binds to the specific domain in RyR2, and then corrects defective inter-domain interactions within RyR2, subsequently inhibits diastolic Ca2+ leak. In turn, dantrolene improves cardiomyocyte function in failing hearts and prevents bidirectional VT induced by injection of epinephrine or exercise in CPVT. Thus, dantrolene may have a potential to treat heart failure and lethal arrhythmia, specifically targeting RyR2.

Research Products

• [Journal Article] Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes (2014)
  • Author(s): Fukuda M, Yamamoto T, Nishimura S, Kato T, Murakami W, Hino A, Ono M, Tateishi H, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M
  • Journal Title: Biochem Biophys Res Commun Volume: (in press)
  • Peer Reviewed
• [Journal Article] A low-doseβ1 blocker effectively and safely slows heart rate in patients with acute decompensated heart failure and rapid atrial fibrillation (2014)
  • Author(s): Kobayashi S, Murakami W, Myoren T, Tateishi H, Okuda S, Doi M, Nao T, Wada Y, Matsuzaki M. Yano M
  • Journal Title: Cardiology Volume: 127 Pages: 105-113
  • Peer Reviewed
• [Journal Article] Sarcomere Gene Mutations Are Associated With Increased Cardiovascular Events in Left Ventricular Hypertrophy (2013)
  • Author(s): Fujita T, Fujino N, Anan R, Tei C, Kubo T, Doi Y, Kinugawa S, Tsutsui H, Kobayashi S, Yano M, Asakura M, Kitakaze M, Komuro I, Konno T, Hayash Hi, Kawashiri M, Ino H, Yamagishi M
  • Journal Title: JACC Heart Failure Volume: 6 Pages: 459-466
  • Peer Reviewed
• [Journal Article] A low-doseβblocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternansin patients with acute decompensated heart failure (2012)
  • Author(s): Kobayashi S, Susa T, Tanaka T, Murakami W, Fukuta S, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Okamura T, Yano M, Matsuzaki M
  • Journal Title: Circ J Volume: 76 Pages: 1646-53
  • Peer Reviewed
• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker for predicting cardiac events and evaluating the effectiveness of carvedilol treatment in patients with chronic systolic heart failure (2012)
  • Author(s): Susa T, Kobayashi S, Tanaka T, Murakami W, Akashi S, Kunitsugu I, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Okamura T, Yano M, Matsuzaki M
  • Journal Title: Circ J Volume: 76 Pages: 117-26
  • Peer Reviewed
• [Journal Article] Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts (2012)
  • Author(s): Hino A, Yano M, Kato T, Fukuda M, Suetomi T, Ono M, Murakami W, Susa T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M
  • Journal Title: Cardiovasc Res Volume: 96 Pages: 433-43
  • Peer Reviewed
• [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca²⁺release leading to catecholaminergic polymorphic ventricular tachycardia (2011)
  • Author(s): Suetomi T, Yano M, Uchinoumi H, Fukuda M, Hino A, Ono M, Xu X, Tateishi H, Okuda S, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M
  • Journal Title: Circulation Volume: 124 Pages: 682-94
  • Peer Reviewed
• [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure (2011)
  • Author(s): Kobayashi S, Susa T, Tanaka T, Wada Y, Okuda S, Doi M, Nao T, Yoshiga Y, Yamada J, Okamura T, Ueyama T, Kawamura S, Yano M, Matsuzaki M
  • Journal Title: Eur J Heart Fail Volume: 13 Pages: 29-36
  • Peer Reviewed
• [Presentation] A Novel Selective EP4 Receptor Agonist Improves Intracellular Ca^<2+> Handling and Cardiomyocyte Function in Intact Failing Cardiomyocytes (2013)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Takeki Myoren, Shigehiko Nishimura, Takayoshi Katoh, Masakazu Fukuda, Makoto Ono, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas, (U.S.A)
  • Year and Date: 20131100
• [Presentation] Elevated Myocardial Oxidative Stress Induced by Catecholamines Related to Transient Left Ventricular Cysfunction in Patients With Takotsubo Cardiomyopathy (2012)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Tadamitsu Nakashima, Hiroki Tateishi, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles, (U.S.A) (Oral)
  • Year and Date: 20121100
• [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine, An Oxidative Stress Marker, Predicts The Inflammatory Activity within the Heart in Patients with Cardiac Sarcoidosis (2012)
  • Author(s): Shigeki Kobayashi, Wakako Murakami, Seiko Fukuta, Masakazu Fukuda, Shinichi Okuda, Tomoko Nao, Masahiro Doi, Yasuaki Wada, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles, (U.S.A) (Oral)
  • Year and Date: 20121100
• [Presentation] Fixing Ca^<2+> Leakage From Cardiac Ryanodine Receptor by Low-dose ofβBlocker Safely Enhances Inotropic Response to Milrinone in Acute Heart Failure (2012)
  • Author(s): Shigeki Kobayashi, Wakako Murakami, Takayoshi Kato, Masakazu Fukuda, Akihiro Hino, Hiroki Tateishi, Takeshi Yamamoto, Takeshi Yamamoto, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 5th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles, (U.S.A) (Oral)
  • Year and Date: 20121100
• [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine as a Novel Marker of Left Ventricular Remodelling in Patients With Dilated Cardiomyopathy (2012)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Takamasa Oda, Hiroki Tateishi, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles, (U.S.A) (Poster)
  • Year and Date: 20121100
• [Presentation] Ryanodine receptor-targeting therapy against heart failure and lethal arrhythmia (2011)
  • Author(s): Shigeki Kobayashi, Masafumi Yano,Takeshi Yamamoto, Masunori Matsuzaki
  • Organizer: The 28th Annual Meeting of the International Society for Heart Research Japanese Section
  • Place of Presentation: The National Center of Science Building(Tokyo) (Symposium)
  • Year and Date: 20111200
• [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine as a Novel Biomarker of Inflammatory Activity in Patients with Cardiac Sarcoidosis : Insight From Immunohistochemical Technique and ^<18>F-FDG PET/CT (2011)
  • Author(s): Seiko Fukuta, Shigeki Kobayashi, Takeo Tanaka, Takehisa Susa, Wakako Murakami, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Jutaro Yamada, Takeshi Ueyama, Takayuki Okamura, Shuji Kawamura,Masafumi Yano, Masunori Matsuzaki
  • Organizer: 84rd Scientific Session of American Heart Association
  • Place of Presentation: Orlando (U.S.A) (Poster) (Circulation.2011 ;124:A10269)
  • Year and Date: 20111100
• [Presentation] Low-dose ofβblocker in combination with milrinone improve cardiac function in patients with acute decompensated heart failure (2011)
  • Author(s): Shigeki Kobayashi, Takehisa Susa,Tanaka Takeo, Wakako Murakami, Shinichi Okuda, Masahiro Doi, Tomoko Nao, Yasuaki Wada, Masafumi Yano, Masunori Matsuzaki
  • Organizer: European Society of Cardiololgy Congress 2011
  • Place of Presentation: Paris(France)(Eur Heart J32[Suppl 1] :785)
  • Year and Date: 20110800
• [Remarks]
  • URL: http://ds.cc.yamaguchi-u.ac.jp/~ninai/result/paper_eng.html