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

To clarify the pharmacological properties of the Na⁺/Ca²⁺ exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K⁺ current (I_Kr) blocker-induced 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 (MAP₉₀) 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 MAP₉₀ 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 MAP₉₀ 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 blocker-induced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

L-type Ca2+ channel; Na+/Ca2+ exchanger; SEA0400; drug-induced long QT syndrome.