Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Markedly Improves the Function of Failing Cardiomyocytes by Stabilizing Interdomain Interactions Within the Ryanodine Receptor

Objectives We sought to investigate the effect of dantrolene, a drug generally used to treat malignant hyperthermia, on the Ca2+ release and cardiomyocyte function in failing hearts. Background The N-terminal (N: 1–600) and central (C: 2000–2500) domains of the ryanodine receptor (RyR) harbor many m...

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Bibliographic Details
Published in:Journal of the American College of Cardiology 2009-05, Vol.53 (21), p.1993-2005
Main Authors: Kobayashi, Shigeki, MD, PhD, Yano, Masafumi, MD, PhD, Suetomi, Takeshi, MD, Ono, Makoto, MD, Tateishi, Hiroki, MD, Mochizuki, Mamoru, MD, PhD, Xu, Xiaojuan, MD, Uchinoumi, Hitoshi, MD, Okuda, Shinichi, MD, PhD, Yamamoto, Takeshi, MD, PhD, Koseki, Noritaka, BS, Kyushiki, Hiroyuki, PhD, Ikemoto, Noriaki, PhD, Matsuzaki, Masunori, MD, PhD
Format: Article
Language:English
Subjects:
Animal diseases
Animals
Biological and medical sciences
Blood pressure
calcium
Calcium - metabolism
Cardiology
Cardiology. Vascular system
Cardiomyocytes
Cardiovascular
Dantrolene - therapeutic use
Disease Models, Animal
Dogs
Heart failure
Heart Failure - drug therapy
Heart Failure - etiology
Heart Failure - physiopathology
Hypotheses
Internal Medicine
Labeling
Lasers
Malignant Hyperthermia - complications
Malignant Hyperthermia - drug therapy
Malignant Hyperthermia - physiopathology
Medical sciences
Membrane Potentials - drug effects
Microscopy
Microscopy, Confocal
Muscle Relaxants, Central - therapeutic use
Musculoskeletal system
Mutation
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Peptides
Ryanodine Receptor Calcium Release Channel - drug effects
Ryanodine Receptor Calcium Release Channel - metabolism
sarcoplasmic reticulum
Treatment Outcome
Ventricular Function, Right - drug effects
Ventricular Function, Right - physiology
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Summary:Objectives We sought to investigate the effect of dantrolene, a drug generally used to treat malignant hyperthermia, on the Ca2+ release and cardiomyocyte function in failing hearts. Background The N-terminal (N: 1–600) and central (C: 2000–2500) domains of the ryanodine receptor (RyR) harbor many mutations associated with malignant hyperthermia in skeletal muscle RyR (RyR1) and polymorphic ventricular tachycardia in cardiac RyR (RyR2). There is strong evidence that interdomain interaction between these regions plays an important role in the mechanism of channel regulation. Methods Sarcoplasmic reticulum vesicles and cardiomyocytes were isolated from the left ventricular muscles of dogs (normal or rapid ventricular pacing for 4 weeks), for Ca2+ leak, transient, and spark assays. To assess the zipped or unzipped state of the interacting domains, the RyR was labeled fluorescently with methylcoumarin acetate in a site-directed manner. We used a quartz-crystal microbalance technique to identify the dantrolene binding site within the RyR2. Results Dantrolene specifically bound to domain 601–620 in RyR2. In the sarcoplasmic reticulum isolated from pacing-induced failing dog hearts, the defective interdomain interaction (domain unzipping) had already occurred, causing spontaneous Ca2+ leak. Dantrolene suppressed both domain unzipping and the Ca2+ leak, demonstrating identical drug concentration-dependence (IC50 = 0.3 μmol/l). In failing cardiomyocytes, both diastolic Ca2+ sparks and delayed afterdepolarization were observed frequently, but 1 μmol/l dantrolene inhibited both events. Conclusions Dantrolene corrects defective interdomain interactions within RyR2 in failing hearts, inhibits spontaneous Ca2+ leak, and in turn improves cardiomyocyte function in failing hearts. Thus, dantrolene may have a potential to treat heart failure, specifically targeting the RyR2.
ISSN:0735-1097
1558-3597
DOI:10.1016/j.jacc.2009.01.065