Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Ahn, H. S., Kim, S. E., Jang, H. J., Kim, M. J., Rhie, D. J., Yoon, S. H., Jo, Y. H., Kim, M. S., Sung, K. W., Kim, S. Y., and Hahn, S. J., Open channel block of Kv1.3 by rosiglitazone and troglitazone: Kv1.3 as the pharmacological target for rosiglitazone. Naunyn Schmiedebergs Arch. Pharmacol., 374, 305–309 (2007).
Chapelsky, M. C., Thompson-Culkin, K., Miller, A. K., Sack, M., Blum, R., and Freed, M. I., Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J. Clin. Pharmacol., 43, 252–259 (2003).
Curran, M. E., Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D., and Keating, M. T., A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell, 80, 795–803 (1995).
Deeks, E. D. and Keam, S. J., Rosiglitazone: a review of its use in type 2 diabetes mellitus. Drugs, 67, 2747–2779 (2007).
Hamill, O. P., Marty, A., Neher, E., Sakmann, B., and Sigworth, F. J., Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch., 391, 85–100 (1981).
Hruska, M. W. and Frye, R. F., Simplified method for determination of rosiglitazone in human plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 803, 317–320 (2004).
Jeong, I., Choi, B., and Hahn, S., Rosiglitazone inhibits Kv 4.3 potassium channels by open-channel block and acceleration of closed-state inactivation. Br. J. Pharmacol., 163, 510–520 (2011).
Jo, S. H., Hong, H. K., Chong, S. H., Won, K. H., Jung, S. J., and Choe, H., Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652. Eur. J. Pharmacol., 592, 19–25 (2008).
Knock, G. A., Mishra, S. K., and Aaronson, P. I., Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes. Eur. J. Pharmacol., 368, 103–109 (1999).
Kolte, B. L., Raut, B. B., Deo, A. A., Bagool, M. A., and Shinde, D. B., Liquid chromatographic method for the determination of rosiglitazone in human plasma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 788, 37–44 (2003).
Lee, S. Y., Kim, Y. J., Kim, K. T., Choe, H., and Jo, S. H., Blockade of HERG human K+ channels and IKr of guineapig cardiomyocytes by the antipsychotic drug clozapine. Br. J. Pharmacol., 148, 499–509 (2006).
Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M., and Kliewer, S. A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem., 270, 12953–12956 (1995).
Lu, L., Reiter, M. J., Xu, Y., Chicco, A., Greyson, C. R., and Schwartz, G. G., Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs. Diabetologia, 51, 675–685 (2008).
Mishra, S. K. and Aaronson, P. I., Differential block by troglitazone and rosiglitazone of glibenclamide-sensitive K+ current in rat aorta myocytes. Eur. J. Pharmacol., 386, 121–125 (1999).
Nissen, S. E. and Wolski, K., Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med., 356, 2457–2471 (2007).
Sanguinetti, M. C. and Jurkiewicz, N. K., Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J. Gen. Physiol., 96, 195–215 (1990).
Suessbrich, H., Schonherr, R., Heinemann, S. H., Attali, B., Lang, F., and Busch, A. E., The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br. J. Pharmacol., 120, 968–974 (1997).
Suessbrich, H., Waldegger, S., Lang, F., and Busch, A. E., Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Lett., 385, 77–80 (1996).
Taglialatela, M., Castaldo, P., Pannaccione, A., Giorgio, G., and Annunziato, L., Human ether-a-gogo related gene (HERG) K+ channels as pharmacological targets: present and future implications. Biochem. Pharmacol., 55, 1741–1746 (1998).
Trudeau, M. C., Warmke, J. W., Ganetzky, B., and Robertson, G. A., HERG, a human inward rectifier in the voltage-gated potassium channel family. Science, 269, 92–95 (1995).
Viskin, S., Long QT syndromes and torsade de pointes. Lancet, 354, 1625–1633 (1999).
Wagstaff, A. J. and Goa, K. L., Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs, 62, 1805–1837 (2002).
Zhou, Z., Gong, Q., Ye, B., Fan, Z., Makielski, J. C., Robertson, G. A., and January, C. T., Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys. J., 74, 230–241 (1998).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, S.H., Sung, M.J., Hahn, S.J. et al. Blockade of human HERG K+ channels by rosiglitazone, an antidiabetic drug. Arch. Pharm. Res. 35, 1655–1664 (2012). https://doi.org/10.1007/s12272-012-0917-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-012-0917-x