Blockade of human HERG K+ channels by rosiglitazone, an antidiabetic drug

• Published in: Archives of pharmacal research Vol. 35; no. 9; pp. 1655 - 1664
• Main Authors: Lee, Seung Ho, Sung, Min Ji, Hahn, Sang June, Kim, Jimok, Min, Gyesik, Jo, Su-Hyun, Choe, Han, Choi, Bok Hee
• Format: Journal Article
• Language: English
• Published: Heidelberg Pharmaceutical Society of Korea 01.09.2012; 대한약학회
• Subjects: embryo (animal); ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; genes; HEK293 Cells; human cell lines; Humans; hypoglycemic agents; Hypoglycemic Agents - pharmacology; inhibitory concentration 50; kidneys; Kinetics; Medicine; Membrane Potentials - drug effects; oral administration; Osmolar Concentration; patch-clamp technique; Patch-Clamp Techniques; patients; Pharmacology/Toxicology; Pharmacy; Potassium Channel Blockers - pharmacology; potassium channels; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Research Article; Thiazolidinediones - pharmacology; 약학; Rosiglitazone; Long QT syndrome; HERG; Cardiotoxicity; Antidiabetic drug
• ISSN: 0253-6269; 1976-3786; 1976-3786
• DOI: 10.1007/s12272-012-0917-x

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 IC 50 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.