Systemic administration of calmodulin antagonist W-7 or protein kinase a inhibitor H-8 prevents torsade de pointes in rabbits

Background - The ventricular arrhythmia torsade de pointes (TdP) occurs after QT interval prolongation and is associated with sudden cardiac death. The afterdepolarizations that initiate TdP are facilitated by protein kinase A and the multifunctional Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase). Methods and Results - In this study, we evaluated the feasibility of suppression of TdP through systemic therapy with kinase inhibitory agents in an established animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits. CaM kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose-dependent fashion (4 of 7 inducible at 25 μmol/kg and 1 of 7 inducible at 50 μmol/kg). Increased intracellular Ca²⁺ has been implicated in the genesis of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP in response to the L-type Ca²⁺ channel agonist BAY K 8644 (300 nmol/kg), suggesting that CaM kinase-independent activation of L- type Ca²⁺ current was not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility without shortening the QT interval, increasing heart rate, or reducing the blood pressure. The protein kinase A antagonist H-8 also caused a dose-dependent reduction in TdP inducibility (5 of 6 at 1 μmol/kg, 4 of 6 at 5 μmol/kg, and 0 of 6 at 10 μmol/kg), but unlike W-7, H-8 did so by shortening the QT interval. Conclusions - These findings show that the acute systemic application of W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may be a viable antiarrhythmic strategy.