Mutations in type 2 ryanodine receptor (RyR2), a Ca²⁺ release channel on the sarcoplasmic reticulum, are known to cause ventricular arrhythmias such as catecholaminergic ventricular tachycardia (CPVT). Because conventional anti-arrhythmic drugs sometimes fail to stop arrhythmias in CPVT patients, development of new antiarrhythmic agents that directly target RyR2 is desired. Recently we have screened a well-characterized chemical compound library and found 2 compounds with RyR2 inhibitory action, riluzole and chloroxylenol. In this study, we aimed to verify the anti-arrhythmic effects of these RyR2 inhibitors using a novel CPVT mouse model (RyR2-I4093V) which was established by screening of an ethylnitrosourea-induced mutagenized mice library. ECG records were obtained from the I4093V mice under anesthesia and drugs were intraperitoneally administered. The I4093V mice showed little arrhythmias at two months of age, but exhibited severe ventricular arrhythmias by β-agonist administration. Moreover, frequent spontaneous arrhythmias were observed without β-stimulation at 4-5 months old. Conventional anti-arrhythmic agents (flecainide, pilsicainide, atenolol) and the two novel RyR2 inhibitors suppressed the spontaneous arrhythmia to varying degrees. Our results indicate that the I4093V mouse is a useful model for evaluation of antiarrhythmic drugs and that RyR2 inhibitors are promising candidates for novel anti-arrhythmic drugs.