BACKGROUND AND PURPOSERosiglitazone 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 Kv4.3 potassium channels. EXPERIMENTAL APPROACHThe interaction of rosiglitazone with cloned Kv4.3 channels stably expressed in Chinese hamster ovary cells was investigated using whole-cell patch-clamp techniques. KEY RESULTSRosiglitazone decreased the currents carried by Kv4.3 channels and accelerated the current inactivation, concentrationdependently, with an IC50 of 24.5 mM. The association and dissociation rate constants for rosiglitazone were 1.22 mM -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 Kv4.3 channels. Rosiglitazone shifted the steady-state inactivation curves in the hyperpolarizing direction, concentration-dependently. The Ki for the interaction between rosiglitazone and the inactivated state of Kv4.3 channels was 1.49 mM, from the concentration-dependent shift in the steady-state inactivation curves. Rosiglitazone also accelerated the kinetics of the closed-state inactivation of Kv4.3 channels. Rosiglitazone did not affect either use dependence or recovery from inactivation of Kv4.3 currents. CONCLUSION AND IMPLICATIONSOur results indicate that rosiglitazone potently inhibits currents carried by Kv4.3 channels by interacting with these channels in the open state and by accelerating the closed-state inactivation of Kv4.3 channels. LINKED ARTICLEThis article is commented on by Hancox, pp. 496-498 of this issue. To view this commentary visit http://dx