Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model

Circ J. 2010 Nov;74(12):2579-84. doi: 10.1253/circj.cj-10-0680. Epub 2010 Oct 7.

Abstract

Background: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca(2+) leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of RyRs. Here, the in vivo anti-arrhythmic effect of dantrolene in a human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2(R2474S/+) knock-in (KI) mouse model was investigated.

Methods and results: ECG was monitored in KI mice (n=6) and wild-type (WT) mice (n=6), before and after an injection of epinephrine (1.0mg/kg) or on exercise using a treadmill. In all KI (but not WT) mice, bi-directional ventricular tachycardia (VT) was induced after an injection of epinephrine or on exercise. Pre-treatment with dantrolene (for 7-10 days) significantly inhibited the inducible VT (P<0.01). In KI cardiomyocytes, Ca(2+) spark frequency (SpF; s(-1)·100µm(-1): 5.8±0.3, P<0.01) was much more increased after the addition of isoproterenol than in WT cardiomyocytes (SpF: 3.6±0.2). The increase in SpF seen in KI cardiomyocytes was attenuated by 1.0µmol/L dantrolene (SpF: 3.6±0.5, P<0.01).

Conclusions: Dantrolene prevents CPVT, presumably by inhibiting Ca(2+) leak through the RyR2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / adverse effects
  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Calcium / metabolism
  • Dantrolene / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electrocardiography
  • Epinephrine / adverse effects
  • Epinephrine / pharmacology
  • Gene Knock-In Techniques
  • Humans
  • Malignant Hyperthermia*
  • Mice
  • Mice, Mutant Strains
  • Muscle Relaxants, Central / pharmacology
  • Myocytes, Cardiac / metabolism
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Tachycardia, Ventricular / chemically induced
  • Tachycardia, Ventricular / drug therapy*
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism*
  • Tachycardia, Ventricular / physiopathology

Substances

  • Adrenergic alpha-Agonists
  • Anti-Arrhythmia Agents
  • Muscle Relaxants, Central
  • Ryanodine Receptor Calcium Release Channel
  • Dantrolene
  • Calcium
  • Epinephrine