The combined ion channel blocker AZD1305 attenuates late Na current and I_Kr -induced action potential prolongation and repolarization instability

To assess the late Na ⁺ current ( I_Nalate ) blockade by the combined ion channel blocker AZD1305 and its influence on repolarization liability in vitro .

Blockade of I_Nalate and the peak Na ⁺ current ( I_Napeak ) by AZD1305 and the effects of E-4031, AZD1305, and lidocaine on repolarization liability following cycle length (CL) changes were examined in dog cardiomyocytes and rabbit-superfused Purkinje fibre (PF) and ventricular muscle (VM) preparations, respectively. In the rabbit preparations, a short–long–short CL sequence was introduced during, and followed by, stimulation at a basic CL of 500 ms in the presence of E-4031, AZD1305, E-4031 + AZD1305, or E-4031 + lidocaine. The standard deviation of the action potential duration at 90% repolarization (APD ₉₀ ) of the five action potentials following resumption of the basic CL was quantified as APD ₉₀ instability. AZD1305 concentration-dependently blocked I_Nalate (IC ₅₀ = 4.3 µM) and I_Napeak (IC ₅₀ = 66 µM). In PFs, E-4031, but not AZD1305, markedly prolonged APD ₉₀ (from 380 ± 15 to 597 ± 86 ms, P < 0.05) after the long CL and augmented APD ₉₀ instability (2 ± 0.4 to 24 ± 6.1 ms, P < 0.05), increases significantly attenuated by AZD1305 and lidocaine. In the VM, the APD ₉₀ prolongation by E-4031 was quantitatively much smaller, thus augmenting the repolarization heterogeneity between the PF and VM, an increase markedly reduced by AZD1305 and lidocaine.

By blocking I_Nalate , AZD1305 attenuates excessive APD ₉₀ prolongation and repolarization instability following sudden slowing of rhythm implying a low proarrhythmic potential for AZD1305.