Blockade of human HERG K⁺ channels by rosiglitazone, an antidiabetic drug.
This study examined the effect of rosiglitazone, an oral antidiabetic drug, on human ether-a-gogo-related gene (HERG) channels expressed in human embryonic kidney (HEK293) cells. Using the whole-cell patch-clamp technique, interaction between rosiglitazone and HERG in HEK293 cells was studied. Rosiglitazone inhibited HERG channels in a concentration-dependent manner, with an IC₅₀ value of 18.8 μM and a Hill coefficient of 1.0. These effects were reversible after wash-out of the drug. The rosiglitazone-induced inhibition of HERG channels was voltagedependent, with a steep increase in inhibition over the voltage range of channel opening. However, inhibition was voltage-independent over the voltage range in which channels are fully activated. Rosiglitazone did not change the steady-state activation or inactivation curves or the activation or deactivation kinetics, implying that rosiglitazone blocks HERG channels predominantly in the open and inactivated state rather than in the closed state. The present study suggests that rosiglitazone blocks HERG channels by binding to activated and inactivated channels, and rosiglitazone use should thus be carefully monitored in patients with pre-existing QT prolongation.
Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, 561-180, Korea.
Seung Ho
SH
Lee
Min Ji
MJ
Sung
Sang June
SJ
Hahn
Jimok
J
Kim
Gyesik
G
Min
Su-Hyun
SH
Jo
Han
H
Choe
Bok Hee
BH
Choi
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007004:Hypoglycemic Agents; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone