The Antiarrhythmic Action of the Na⁺/Ca²⁺ Exchanger Inhibitor SEA0400 on Drug-Induced Long QT Syndrome Depends on the Severity of Proarrhythmic Conditions in Anesthetized Atrioventricular Block Rabbits

Abstract

To clarify the pharmacological properties of the Na /Ca 2 exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K current (I Kr ) blockerinduced torsade de pointes (TdP) in isoflurane-anesthetized rabbits. Atrioventricular block was induced in rabbits using a catheter ablation technique, and the monophasic action potential (MAP) of the right ventricle was measured under electrical pacing at 60 beats/min. In non-treated control animals, intravenous administration of low-dose (0.3 mg/kg) or high-dose nifekalant (3 mg/kg) prolonged the MAP duration (MAP 90 ) by 113 11 ms (n 5) and 237 39 ms (n 5), respectively, where TdP was induced in 1/5 animals treated with a low dose and in 3/5 animals treated with a high dose of nifekalant. In SEA0400-treated animals, low-and high-dose nifekalant prolonged the MAP 90 by 65 13 ms (n 5) and 230 20 ms (n 5), respectively. No TdP was induced by the low dose but 1/5 animals treated with a high dose of nifekalant developed TdP. In verapamil-treated animals, low-dose and high-dose nifekalant prolonged MAP 90 by 50 12 ms (n 5) and 147 30 ms (n 5), respectively, without inducing TdP. These results suggest that SEA0400 has the potential to inhibit low-dose nifekalant-induced TdP by suppressing the MAP-prolonging action of nifekalant, whereas the drug inhibited high-dose nifekalant-induced TdP without affecting the MAP-prolonging action of nifekalant. This may reveal that, in contrast to verapamil, the antiarrhythmic effects of SEA0400 on I Kr blockerinduced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

Ion channel trafficking implications in heart failure

“…Studies have also demonstrated an upregulation of both mRNA and protein expression of NCX in human and animal models, contributing to the arrhythmogenicity of HF ( 86 ). These changes are associated with arrhythmogenic mechanisms, such as early (EADs) and delayed afterdepolarizations (DADs) in HF ( 87 , 88 ). Therefore, the block of NCX may represent a potential therapy for the prevention of arrhythmia in HF ( 85 ).…”