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.