Rosiglitazone inhibits K _v4.3 potassium channels by open-channel block and acceleration of closed-state inactivation

BACKGROUND AND PURPOSE Rosiglitazone is a widely used oral hypoglycaemic agent, which improves insulin resistance in type 2 diabetes. Chronic rosiglitazone treatment is associated with a number of adverse cardiac events. The present study was designed to characterize the effects of rosiglitazone on cloned K _v4.3 potassium channels. EXPERIMENTAL APPROACH The interaction of rosiglitazone with cloned K _v4.3 channels stably expressed in Chinese hamster ovary cells was investigated using whole-cell patch-clamp techniques. KEY RESULTS Rosiglitazone decreased the currents carried by K _v4.3 channels and accelerated the current inactivation, concentration-dependently, with an IC ₅₀ of 24.5 μM. The association and dissociation rate constants for rosiglitazone were 1.22 μM ^-1·s ^-1 and 31.30 s ^-1 respectively. Block by rosiglitazone was voltage-dependent, increasing in the voltage range for channel activation; however, no voltage dependence was found in the voltage range required for full activation. Rosiglitazone had no effect on either the deactivation kinetics or the steady-state activation of K _v4.3 channels. Rosiglitazone shifted the steady-state inactivation curves in the hyperpolarizing direction, concentration-dependently. The K _i for the interaction between rosiglitazone and the inactivated state of K _v4.3 channels was 1.49 μM, from the concentration-dependent shift in the steady-state inactivation curves. Rosiglitazone also accelerated the kinetics of the closed-state inactivation of K _v4.3 channels. Rosiglitazone did not affect either use dependence or recovery from inactivation of K _v4.3 currents. CONCLUSION AND IMPLICATIONS Our results indicate that rosiglitazone potently inhibits currents carried by K _v4.3 channels by interacting with these channels in the open state and by accelerating the closed-state inactivation of K _v4.3 channels.