Rosiglitazone inhibits K_v4.3 potassium channels by open‐channel block and acceleration of closed‐state inactivation

Abstract

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

Cardiac ion channel modulation by the hypoglycaemic agent rosiglitazone

“…Moreover, in healthy individuals, maximal plasma rosiglitazone concentrations following a single 8 mg oral dose of the drug reach approximatelỹ 370-700 ng·mL -1 (equivalent to~1-2 mM; ThompsonCulkin et al, 2002;Park et al, 2004). Thus, the majority of acute ion channel inhibitory effects seen in the two studies reported here (Jeong et al, 2011;Szentandrássy et al, 2011) occur at higher drug concentrations than are likely to occur in vivo, except -as noted by Szentandrássy et al (2011) potentially in overdose. An exception to this is inactivation state-dependent inhibition of Kv4.3 /ITO, as the Ki for this action of the drug occurs at clinically relevant concentrations (Jeong et al, 2011).…”

“…The second rosiglitazone study in this issue by Jeong et al (2011) is complementary to that by Szentandrássy et al (2011), in that it provides increased insight into the likely basis of I TO inhibition by rosiglitazone. Recombinant Kv4.3 channel current was inhibited with an IC50 (half maximal inhibitory concentration) of~25 mM (Jeong et al, 2011), which is in strong agreement with the observed potency of inhibition of native ITO (Szentandrássy et al, 2011).…”

“…Szentandrássy et al (2011) have focused on establishing the effects of the drug on ventricular action potentials and major ventricular ionic currents from a large (canine) animal model; Jeong et al (2011) have focused on studying recombinant K v4.3 channels, as this Kv channel subtype is involved in mediating transient outward potassium current (ITO) that contributes significantly to the early phase of repolarization of ventricular action potentials (see Dixon et al, 1996).…”

“…Recombinant Kv4.3 channel current was inhibited with an IC50 (half maximal inhibitory concentration) of~25 mM (Jeong et al, 2011), which is in strong agreement with the observed potency of inhibition of native ITO (Szentandrássy et al, 2011). Voltagedependent activation of Kv4.3 channels was little-affected by the drug, but voltage-dependent inactivation was negatively voltage-shifted in a concentration-dependent manner, from which an apparent dissociation constant (Ki) for inactivated channels of~1.5 mM was estimated (Jeong et al, 2011). Closed state inactivation of Kv4.3 channels was also accelerated by the drug (Jeong et al, 2011).…”

“…Voltagedependent activation of Kv4.3 channels was little-affected by the drug, but voltage-dependent inactivation was negatively voltage-shifted in a concentration-dependent manner, from which an apparent dissociation constant (Ki) for inactivated channels of~1.5 mM was estimated (Jeong et al, 2011). Closed state inactivation of Kv4.3 channels was also accelerated by the drug (Jeong et al, 2011).…”