Korean J Physiol Pharmacol.  2022 Mar;26(2):135-144. 10.4196/kjpp.2022.26.2.135.

The antidiabetic drug rosiglitazone blocks Kv1.5 potassium channels in an open state

• Lee HM
• Hahn SJ
• Choi BH

• KMID: 2526732
• DOI: http://doi.org/10.4196/kjpp.2022.26.2.135

Abstract

An antidiabetic drug, rosiglitazone is a member of the drug class of thiazolidinedione. Although restrictions on use due to the possibility of heart toxicity have been removed, it is still a drug that is concerned about side effects on the heart. We here examined, using Chinese hamster ovary cells, the action of rosiglitazone on Kv1.5 channels, which is a major determinant of the duration of cardiac action potential. Rosiglitazone rapidly and reversibly inhibited Kv1.5 currents in a concentrationdependent manner (IC ₅₀ = 18.9 µM) and accelerated the decay of Kv1.5 currents without modifying the activation kinetics. In addition, the deactivation of Kv1.5 current, assayed with tail current, was slowed by the drug. All of the results as well as the usedependence of the rosiglitazone-mediated blockade indicate that rosiglitazone acts on Kv1.5 channels as an open channel blocker. This study suggests that the cardiac side effects of rosiglitazone might be mediated in part by suppression of Kv1.5 channels, and therefore, raises a concern of using the drug for diabetic therapeutics.

Keyword

Cardiotoxicity; Ion channel; Kv1.5 channel; Open channel block; Rosiglitazone

Figure

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  Fig. 1 Concentration dependence of rosiglitazone-induced inhibition of Kv1.5 currents. (A) Kv1.5 currents were elicited with +50 mV depolarization (250 ms) from a holding potential of –80 mV, every 10 sec. Currents recorded in the absence and presence of 3, 10, 30, and 100 µM rosiglitazone were superimposed. The dotted line represents zero current. (B) Dose response curve of rosiglitazone-mediated reduction in Kv1.5 current. The amplitudes of Kv1.5 current were measured at the end (closed circle) and peak (open circle) of the depolarizing pulses at various concentrations of rosiglitazone. The data of % inhibition (I [%] = [1 – Irosiglitazone/Icontrol] × 100) were fitted with the Hill equation (solid lines). (C) Time course of Kv1.5 inhibition by rosiglitazone. The current amplitudes were measured at the end of a 250-ms depolarizing pulse and normalized to the baseline amplitude. Data are expressed as mean ± SEM.

• 

  Fig. 2 Voltage dependence of rosiglitazone-induced inhibition of Kv1.5 currents. The Kv1.5 currents were produced by applying 250-ms depolarizing pulses between –60 and +40 mV in 10-mV increments every 10 sec from a holding potential of –80 mV under control conditions (A), and after the addition of 20 µM rosiglitazone (B). The dotted lines in (A) and (B) represent zero current. (C) The amplitudes of Kv1.5 currents were measured at the end of test pulses and plotted against membrane potentials, in control (○) and 20 µM rosiglitazone (●). (D) The activation curve of control Kv1.5 current was constructed from tail current amplitudes at –40 mV after 250-ms depolarizing pulses between –60 and +40 mV in 10-mV. Only the Boltzmann fitting curve is shown (dotted line, normalized current y-axis for activation curve). The percent inhibition of Kv1.5 current by rosiglitazone was plotted (●) for comparison with the activation profile. In the voltage range between –20 and 0 mV, the percent inhibition increased steeply suggesting an open channel blockade. The solid line was drawn from a linear curve fitting the relative current data between 0 and +40 mV. Data are expressed as mean ± SEM.

• 

  Fig. 3 Concentration-dependent kinetics of Kv1.5 inhibition caused by rosiglitazone. (A) Kv1.5 currents were elicited with +50 mV pulses (250 ms) every 10 sec in the presence of rosiglitazone (10, 30, and 100 µM). The dotted line represents zero current. (B) A drug-induced time constant (τD) was obtained from a single exponential fitting to the decaying phase of Kv1.5 current. The inverse of τD obtained at +50 mV was plotted against rosiglitazone concentrations. The solid line represents linear fit of the data. A binding rate constant (k+1) and an unbinding rate constant (k–1) were obtained from the slope and intercept values of the fitted line, 1/τD = k+1[D] + k–1. Data are expressed as mean ± SEM.

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  Fig. 4 Effects of rosiglitazone on the deactivation kinetics of Kv1.5 currents. Tail currents were induced with the repolarizing pulse of –40 mV after a 250-ms depolarizing pulse of +50 mV, in the absence and presence of 20 µM rosiglitazone. Superimposition of two tail currents revealed tail crossover (arrow). The dotted line represents zero current. Inset, mean time constants of the tail current decay in the presence of rosiglitazone was significantly larger than that in control condition (Student’s t-test, n = 4; *p < 0.05).

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  Fig. 5 Use-dependence of rosiglitazone-mediated inhibition of Kv1.5. (A) Superimposed Kv1.5 current traces elicited successively with depolarizing pulses (+50 mV, 125 ms) at 1 or 2 Hz. The dotted lines represent zero current. Dashed lines are for a comparison of the peak amplitudes of the first currents in both stimuli sets. (B) Plot of normalized amplitude of peak current 1 (circles) and 2 Hz (triangles), in control (open symbols) and in 20 µM rosiglitazone (closed symbols), against the elapsed time axis. The peak amplitudes were normalized to the peak amplitude of the first current in each condition. (C) With the data in (B), the current amplitude in rosiglitazone was normalized to the control amplitude at each elapsed time. Data are expressed as mean ± SEM.

• 

  Fig. 6 Effects of rosiglitazone on the kinetics of Kv1.5 recovery from steady-state inactivation. (A) The degree of recovery was assayed with the following two-pulse protocol: the first prepulse (+40 mV, 250 ms) was followed by a second identical pulse with a varying interpulse interval ranging from 5 to 10,000 ms. The pair of pulses was applied at an interval of 30 sec. (B) The peak amplitude of the second current in the pair (■ in A) was normalized to the peak of the first current (□ in A), and plotted against interpulse intervals. (C) The range of y-axis values in (B) were expanded to the range from 0 to 1 by normalizing the minimum values in (B) (at 5 ms interval) to 0. This re-normalization revealed faster recovery from inactivation in rosiglitazone than in control condition. The curves in (B and C) were obtained from a double exponential fitting, from which two recovery time constants were obtained. (D) Summarized data of the fast and slow time constants obtained from the double exponential fittings (n = 4; *p < 0.05 vs. data under control conditions). Data are expressed as means ± SEM.

Reference

1. Deeks ED, Keam SJ. 2007; Rosiglitazone: a review of its use in type 2 diabetes mellitus. Drugs. 67:2747–2779. DOI: 10.2165/00003495-200767180-00008. PMID: 18062722.

2. Wagstaff AJ, Goa KL. 2002; Rosiglitazone: a review of its use in the management of type 2 diabetes mellitus. Drugs. 62:1805–1837. DOI: 10.2165/00003495-200262120-00007. PMID: 12149047.

3. Nissen SE, Wolski K. 2007; Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 356:2457–2471. Erratum in: N Engl J Med. 2007;357:100. DOI: 10.1056/NEJMoa072761. PMID: 17517853.

4. Lebovitz HE. 2019; Thiazolidinediones: the forgotten diabetes medications. Curr Diab Rep. 19:151. DOI: 10.1007/s11892-019-1270-y. PMID: 31776781. PMCID: PMC6881429.

5. Eto K, Ohya Y, Nakamura Y, Abe I, Fujishima M. 2001; Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle. Eur J Pharmacol. 423:1–7. DOI: 10.1016/S0014-2999(01)01047-0. PMID: 11438300.

6. Knock GA, Mishra SK, Aaronson PI. 1999; Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes. Eur J Pharmacol. 368:103–109. DOI: 10.1016/S0014-2999(99)00020-5. PMID: 10096775.

7. Ahn HS, Kim SE, Jang HJ, Kim MJ, Rhie DJ, Yoon SH, Jo YH, Kim MS, Sung KW, Kim SY, Hahn SJ. 2007; 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. DOI: 10.1007/s00210-006-0118-6. PMID: 17119927.

8. Jeong I, Choi BH, Hahn SJ. 2011; Rosiglitazone inhibits Kv4.3 potassium channels by open-channel block and acceleration of closed-state inactivation. Br J Pharmacol. 163:510–520. DOI: 10.1111/j.1476-5381.2011.01210.x. PMID: 21232039. PMCID: PMC3101614.

9. Overturf KE, Russell SN, Carl A, Vogalis F, Hart PJ, Hume JR, Sanders KM, Horowitz B. 1994; Cloning and characterization of a Kv1.5 delayed rectifier K⁺ channel from vascular and visceral smooth muscles. Am J Physiol. 267(5 Pt 1):C1231–C1238. DOI: 10.1152/ajpcell.1994.267.5.C1231. PMID: 7977686.

10. Tamkun MM, Knoth KM, Walbridge JA, Kroemer H, Roden DM, Glover DM. 1991; Molecular cloning and characterization of two voltage-gated K⁺ channel cDNAs from human ventricle. FASEB J. 5:331–337. DOI: 10.1096/fasebj.5.3.2001794. PMID: 2001794.

11. Deal KK, England SK, Tamkun MM. 1996; Molecular physiology of cardiac potassium channels. Physiol Rev. 76:49–67. DOI: 10.1152/physrev.1996.76.1.49. PMID: 8592732.

12. Colatsky TJ, Follmer CH, Starmer CF. 1990; Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation. 82:2235–2242. DOI: 10.1161/01.CIR.82.6.2235. PMID: 2242545.

13. Li GR, Feng J, Wang Z, Fermini B, Nattel S. 1996; Adrenergic modulation of ultrarapid delayed rectifier K⁺ current in human atrial myocytes. Circ Res. 78:903–915. DOI: 10.1161/01.RES.78.5.903. PMID: 8620611.

14. Wang Z, Fermini B, Nattel S. 1993; Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K⁺ current similar to Kv1.5 cloned channel currents. Circ Res. 73:1061–1076. DOI: 10.1161/01.RES.73.6.1061. PMID: 8222078.

15. Cobbe SM. 1994; Incidence and risks associated with atrial fibrillation. Pacing Clin Electrophysiol. 17(5 Pt 2):1005–1010. DOI: 10.1111/j.1540-8159.1994.tb01453.x. PMID: 7518586.

16. Swanson R, Marshall J, Smith JS, Williams JB, Boyle MB, Folander K, Luneau CJ, Antanavage J, Oliva C, Buhrow SA, Bennet C, Stein RB, Kaczmarek LK. 1990; Cloning and expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain. Neuron. 4:929–939. DOI: 10.1016/0896-6273(90)90146-7. PMID: 2361015.

17. Choi BH, Choi JS, Jeong SW, Hahn SJ, Yoon SH, Jo YH, Kim MS. 2000; Direct block by bisindolylmaleimide of rat Kv1.5 expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther. 293:634–640. PMID: 10773038.

18. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. 1981; Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 391:85–100. DOI: 10.1007/BF00656997. PMID: 6270629.

19. Snyders DJ, Yeola SW. 1995; Determinants of antiarrhythmic drug action. Electrostatic and hydrophobic components of block of the human cardiac hKv1.5 channel. Circ Res. 77:575–583. DOI: 10.1161/01.RES.77.3.575. PMID: 7641327.

20. Delpón E, Valenzuela C, Gay P, Franqueza L, Snyders DJ, Tamargo J. 1997; Block of human cardiac Kv1.5 channels by loratadine: voltage-, time- and use-dependent block at concentrations above therapeutic levels. Cardiovasc Res. 35:341–350. DOI: 10.1016/S0008-6363(97)00121-1. PMID: 9349397.

21. Valenzuela C, Delpón E, Franqueza L, Gay P, Pérez O, Tamargo J, Snyders DJ. 1996; Class III antiarrhythmic effects of zatebradine. Time-, state-, use-, and voltage-dependent block of hKv1.5 channels. Circulation. 94:562–570. DOI: 10.1161/01.CIR.94.3.562. PMID: 8759103.

22. Franqueza L, Valenzuela C, Delpón E, Longobardo M, Caballero R, Tamargo J. 1998; Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br J Pharmacol. 125:969–978. DOI: 10.1038/sj.bjp.0702129. PMID: 9846634. PMCID: PMC1565661.

23. Park J, Cho KH, Lee HJ, Choi JS, Rhie DJ. 2020; Open channel block of Kv1.4 potassium channels by aripiprazole. Korean J Physiol Pharmacol. 24:545–553. DOI: 10.4196/kjpp.2020.24.6.545. PMID: 33093275. PMCID: PMC7585592.

24. Lee HM, Hahn SJ, Choi BH. 2016; Blockade of Kv1.5 by paroxetine, an antidepressant drug. Korean J Physiol Pharmacol. 20:75–82. DOI: 10.4196/kjpp.2016.20.1.75. PMID: 26807026. PMCID: PMC4722194.

25. Lee HM, Hahn SJ, Choi BH. 2016; Blockade of Kv1.5 channels by the antidepressant drug sertraline. Korean J Physiol Pharmacol. 20:193–200. DOI: 10.4196/kjpp.2016.20.2.193. PMID: 26937216. PMCID: PMC4770110.

26. Kolte BL, Raut BB, Deo AA, Bagool MA, Shinde DB. 2003; Liquid chromatographic method for the determination of rosiglitazone in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 788:37–44. DOI: 10.1016/S1570-0232(02)01011-5. PMID: 12668069.

27. Miles PD, Barak Y, Evans RM, Olefsky JM. 2003; Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding. Am J Physiol Endocrinol Metab. 284:E618–E626. DOI: 10.1152/ajpendo.00312.2002. PMID: 12556354.

28. Tontonoz P, Spiegelman BM. 2008; Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 77:289–312. DOI: 10.1146/annurev.biochem.77.061307.091829. PMID: 18518822.

29. Lebovitz HE, Banerji MA. 2001; Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 56:265–294. DOI: 10.1210/rp.56.1.265. PMID: 11237217.

30. Fedida D, Eldstrom J, Hesketh JC, Lamorgese M, Castel L, Steele DF, Van Wagoner DR. 2003; Kv1.5 is an important component of repolarizing K⁺ current in canine atrial myocytes. Circ Res. 93:744–751. DOI: 10.1161/01.RES.0000096362.60730.AE. PMID: 14500335.

31. Chapelsky MC, Thompson-Culkin K, Miller AK, Sack M, Blum R, Freed MI. 2003; Pharmacokinetics of rosiglitazone in patients with varying degrees of renal insufficiency. J Clin Pharmacol. 43:252–259. DOI: 10.1177/0091270002250602. PMID: 12638393.

32. Hruska MW, Frye RF. 2004; Simplified method for determination of rosiglitazone in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 803:317–320. DOI: 10.1016/j.jchromb.2004.01.010. PMID: 15063342.