Rosiglitazone inhibits Kv4.3 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(v)4.3 potassium channels.

EXPERIMENTAL APPROACH

The interaction of rosiglitazone with cloned K(v)4.3 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(v)4.3 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(v)4.3 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(v)4.3 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(v)4.3 channels. Rosiglitazone did not affect either use dependence or recovery from inactivation of K(v)4.3 currents.

CONCLUSION AND IMPLICATIONS

Our results indicate that rosiglitazone potently inhibits currents carried by K(v)4.3 channels by interacting with these channels in the open state and by accelerating the closed-state inactivation of K(v)4.3 channels.