Background Spontaneous calcium release evoking delayed after-depolarization is believed to cause CPVT, a lethal human arrhythmia provoked by exercise or emotional stress. Beta-adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation and/or sympathetic denervation. Objective To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the CASQ2Δ/Δ mouse model of CPVT2. Methods A heart telemetry device was implanted for continuous ECG recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by western blotting and confocal microscopy. Results Adult CASQ2Δ/Δ mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. Beta adrenergic blockers, propranolol and metoprolol attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with alpha blocking activity, phentolamine or labetalol, abolished both exercise and epinephrine-induced arrhythmia. To the contrary, injection of alpha adrenergic agonist phenylephrine reproducibly provoked VT. Isolated cardiomyocytes from CASQ2Δ/Δ mice had delayed calcium release waves upon exposure to sympathetic agonists which was abolished by phentolamine. Hearts of calsequestrin mutant mice expressed more alpha adreno-receptor1 compared to controls (p<0.05). Conclusions We identified a contribution of alpha adrenergic pathway to pathogenesis of catecholamine-induced arrhythmia. Alpha blockade emerges an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to beta blockers.