Effects of Irbesartan on Cloned Potassium Channels Involved in Human Cardiac Repolarization

Abstract

We studied the effects of irbesartan, a selective angiotensin II type 1 receptor antagonist, on human ether-a-go-go-related gene (HERG), KvLQT1+minK, hKv1.5, and Kv4.3 channels using the patch-clamp technique. Irbesartan exhibited a low affinity for HERG and KvLQT1+minK channels (IC₅₀ = 193.0 ± 49.8 and 314.6 ± 85.4 μM, respectively). In hKv1.5 channels, irbesartan produced two types of block, depending on the concentration tested. At 0.1 μM, irbesartan inhibited the current in a time-dependent manner (22 ± 3.9% at +60 mV). The blockade increased steeply with channel activation increasing at more positive potentials. However, at 10 μM, irbesartan induced a time-independent blockade that occurred in the range of potentials of channel opening, reaching its maximum at ≈0 mV, and remaining unchanged at more positive potentials (24.0 ± 1.0% at +60 mV). In Kv4.3 currents, irbesartan produced a concentration-dependent block, which resulted in two IC₅₀values (1.0 ± 0.1 nM and 7.2 ± 0.6 μM). At 1 μM, it inhibited the peak current and accelerated the time course of inactivation, decreasing the total charge crossing the membrane (36.6 ± 7.8% at +50 mV). Irbesartan shifted the inactivation curve of Kv4.3 channels, the blockade increasing as the amount of inactivated channels increased. Molecular modeling was used to define energy-minimized dockings of irbesartan to hKv1.5 and HERG channels. In conclusion, irbesartan blocks Kv4.3 and hKv1.5 channels at therapeutic concentrations, whereas the blockade of HERG and KvLQT1+minK channels occurred only at supratherapeutic levels. In hKv1.5, a receptor site is apparent on each α-subunit of the channel, whereas in HERG channels a common binding site is present at the pore.