title: Rosiglitazone inhibits Kv4.3 potassium channels by open-channel block and acceleration of closed-state inactivation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology, Medical Research Centre, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: I
authors.initials: I
authors.lastname: Jeong
authors.forename: B H
authors.initials: BH
authors.lastname: Choi
authors.forename: S J
authors.initials: SJ
authors.lastname: Hahn
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors; D018408:Patch-Clamp Techniques; D000077154:Rosiglitazone; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors*; D045162:Thiazolidinediones / Q000009:adverse effects*; D013997:Time Factors
chemical_list: D007004:Hypoglycemic Agents; D051664:Kv1.3 Potassium Channel; D051672:Shal Potassium Channels; D045162:Thiazolidinediones; D000077154:Rosiglitazone