Abstract Body: Background: Dantrolene has been reported to suppress diastolic Ca²⁺ leakage through the cardiac ryanodine receptor (RyR2) by restoring defective inter-subunit interactions within RyR2 and enhancing the binding affinity of calmodulin (CaM) to RyR2. Here, we investigated whether chronic administration of dantrolene which was started after myocardial infarction (MI) inhibits ventricular tachycardia (VT) and alleviates left ventricular remodeling.
Methods: We developed MI model by left anterior descending coronary artery (LAD) ligation in mice. Wild type mice were divided into 4 groups; sham-operated mice (WT-Sham), sham-operated mice treated with dantrolene (WT-Sham-DAN, 20mg/kg/day, i.p.), MI mice (WT-MI) and MI mice treated with dantrolene (WT-MI-DAN). Then, they were followed up for 12 weeks.
Results: The 12-week survival rate was significantly higher in MI-DAN group (71 %) than in WT-MI (40%). Serial echocardiography showed that adverse LV remodeling was ameliorated in WT-MI-DAN group compared to WT-MI group (WT-MI 6.3 ± 0.25 mm, WT-MI-DAN 5.5 ± 0.14 mm, P<0.01). VT test by epinephrine (2mg/kg, i.p.) showed that VT was induced in all WT-MI group, although it was significantly inhibited in WT-MI-DAN group.
An increase in diastolic Ca²⁺ spark frequency and a decrease in sarcoplasmic reticulum Ca²⁺ content were observed in isolated cardiomyocytes from WT-MI group whereas both were significantly ameliorated in WT-MI-DAN group.
Conclusions: Dantrolene improves the diastolic Ca²⁺ leakage from sarcoplasmic reticulum of damaged cardiomyocytes. Chronic administration of dantrolene after MI inhibits VT and ameliorates LV remodeling, leading to improved prognosis after MI. RyR2-targeting therapy could be a novel strategy for the treatment of post MI.