Abstract
Aim:
To investigate the effects of diltiazem, an L-type calcium channel blocker, and propafenone, a sodium channel blocker, on the inactivation and recovery kinetics of fKv1.4, a potassium channel that generates the cardiac transient outward potassium current.
Methods:
The cRNA for fKv1.4ΔN, an N-terminal deleted mutant of the ferret Kv1.4 potassium channel, was injected into Xenopus oocytes to express the fKv1.4ΔN channel in these cells. Currents were recorded using a two electrode voltage clamp technique.
Results:
Diltiazem (10 to 1000 μmol/L) inhibited the fKv1.4ΔN channel in a frequency-dependent, voltage-dependent, and concentration-dependent manner, suggesting an open channel block. The IC50 was 241.04±23.06 μmol/L for the fKv1.4ΔN channel (at +50 mV), and propafenone (10 to 500 μmol/L) showed a similar effect (IC50=103.68±10.13 μmol/L). After application of diltiazem and propafenone, fKv1.4ΔN inactivation was bi-exponential, with a faster drug-induced inactivation and a slower C-type inactivation. Diltiazem increased the C-type inactivation rate and slowed recovery in fKv1.4ΔN channels. However, propafenone had no effect on either the slow inactivation time constant or the recovery.
Conclusion:
Diltiazem and propafenone accelerate the inactivation of the Kv1.4ΔN channel by binding to the open state of the channel. Unlike propafenone, diltiazem slows the recovery of the Kv1.4ΔN channel.
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References
Campbell DL, Rasmusson RL, Qu Y, Strauss HC . The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. I. Basic characterization and kinetic analysis. J Gen Physiol 1993; 101: 60–6.
Greenstein JL, Wu R, Po S, Tomaselli GF, Winslow RL . Role of the calcium-independent transient outward current Ito1 in shaping action potential morphology and duration. Circ Res 2000; 87: 1026–33.
Wettwer E, Amos GJ, Posival H, Ravens U . Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin. Circ Res 1994; 75: 473–82.
Holmgren M, Jurman ME, Yellen G . N-type inactivation and the S4-S5 region of the Shaker K+ channel. J Gen Physiol 1996; 108: 195–206.
Hoshi T, Zagotta WN, Aldrich RW . Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 1990; 250: 533–8.
Isacoff EY, Jan YN, Jan LY . Putative receptor for the cytoplasmic inactivation gate in the Shaker K+ channel. Nature 1991; 353: 86–90.
Jerng HH, Covarrubias M . K+ channel inactivation mediated by the concerted action of the cytoplasmic N- and C-terminal domains. Biophys J 1997; 72: 163–74.
Lopez GA, Jan YN, Jan LY . Evidence that the S6 segment of the Shaker voltage-gated K+ channel comprises part of the pore. Nature 1994; 367: 179–82.
Zagotta WN, Hoshi T, and Aldrich RW . Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB. Science 1990; 250: 568–71.
Liu Y, Jurman ME, Yellen G . Dynamic rearrangement of the outer mouth of a K+ channel during gating. Neuron 1996; 16: 859–67.
Rasmusson RL, Morales MJ, Castellino RC, Zhang Y, Campbell DL, Strauss HC . C-type inactivation controls recovery in a fast inactivating cardiac K+ channel (Kv1.4) expressed in Xenopus oocytes. J Physiol 1995; 489: 709–21.
Kumar S, Hall RJ . Drug treatment of stable angina pectoris in the elderly: defining the place of calcium channel antagonists. Drugs Aging 2003; 20: 805–15.
Hohnloser SH, Kuck KH, Lilienthal J . Rhythm or rate control in atrial fibrillation -pharmacological intervention in atrial fibrillation (PIAF): a randomised trial. Lancet 2000; 356: 1789–94.
Gorenek B, Cavusoglu Y, Goktekin O, Birdane A, Kudaiberdieva G, Ata N, et al. Amiodarone versus sotalol and propafenone for prevention of immediate recurrence of atrial fibrillation after internal cardioversion: importance of P wave analysis. Int J Cardiol 2006; 106: 268–9.
Grissmer S, Nguyen AN, Aiyar J, Hanson DC, Mather RJ, Gutman GA, et al. Pharmacological characterization of five cloned voltage gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol Pharmacol 1994; 45: 1227–34.
Rolf S, Haverkamp W, Borggrefe M, Musshoff U, Eckardt L, Mergenthaler J, et al. Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 22–31.
Caballero R, Gómez R, Núñez L, Moreno I, Tamargo J, Delpón E . Diltiazem inhibits hKv1.5 and Kv4.3 currents at therapeutic concentrations. Cardiovasc Res 2004; 64: 457–66.
Xu L, Huang C, Chen J, Jiang X, Li X, Bett GC, et al. Effect of amiodarone on Kv1.4 channel C-type inactivation: comparison of its effects with those induced by propafenone and verapamil. Pharmazie 2008; 63: 475–9.
Comer MB, Campbell DL, Rasmusson RL, Lamson DR, Morales MJ, Zhang Y, et al. Cloning and characterization of an Ito-like potassium channel from ferret ventricle. Am J Physiol 1994; 267: H1383–95.
Wang S, Morales MJ, Qu YJ, Bett GC, Strauss HC, Rasmusson RL . Kv1.4 channel block by quinidine: evidence for a drug induced allosteric effect. J Physiol 2003; 546: 387–401.
Madeja M, Leicher T, Friederich P, Punke MA, Haverkamp W, Musshoff U, et al. Molecular site of action of the antiarrhythmic drug propafenone at the voltage-operated potassium channel Kv2.1. Mol Pharmacol 2003; 63: 547–56.
Arias C, González T, Moreno I, Caballero R, Delpón E, Tamargo J, et al. Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on hERG channels. Cardiovasc Res 2003; 57: 660–9.
Franqueza L, Valenzuela C, Delpón E, Longobardo M, Caballero R, Tamargo J . Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br J Pharmacol 1998; 125: 969–78.
Paul AA, Witchel HJ, Hancox JC . Inhibition of the current of heterologously expressed hERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br J Pharmacol 2002; 136: 717–29.
Gao Z, Sun H, Chiu SW, Lau CP, Li GR . Effects of diltiazem and nifedipine on transient outward and ultra rapid delayed rectifier potassium currents in human atrial myocytes. Br J Pharmacol 2005; 144: 595–604.
Duan D, Fermini B, Nattel S . Potassium channel blocking properties of propafenone in rabbit atrial myocytes. J Pharmacol Exp Ther 1993; 264: 1113–23.
Hoppe UC, Beuckelmann DJ . Modulation of the hyperpolarization activated inward current (If) by antiarrhythmic agents in isolated human atrial myocytes. Nauny Schmiedebergs Arch Pharmacol 1998; 358: 635–40.
Satoh H, Hashimoto K . Effect of propafenone on the membrane currents of rabbit sino-atrial node cells. Eur J Pharmacol 1984; 99: 185–91.
Delpon E, Valenzuela C, Perez O, Casis O, Tamargo J . Propafenone preferentially blocks the rapidly activating component of delayed rectifier K+ current in guinea pig ventricular myocytes. Voltage-independent and time-dependent block of the slowly activating component. Circ Res 1995; 76: 223–35.
Snyders J, Knoth KM, Roberds SL, Tamkun MM . Time-, voltage-, and state-dependent block by quinidine of a cloned human cardiac potassium channel. Mol Pharmacol 1992; 41: 322–30.
Slawsky MT, Castle NA . K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes. J Pharmacol Exp Ther 1994; 269: 66–74.
Wang S, Morales MJ, Liu S, Strauss HC, Rasmusson RL . Modulation of hERG affinity for E-4031 by [K+]o and C-type inactivation. FEBS Lett 1997; 417: 43–47.
Nerbonne JM, Nichols CG, Schwarz TL, Escande D . Genetic manipulation of cardiac K+ channel function in mice: what have we learned, and where do we go from here? Circ Res 2001; 89: 944–56.
Strauss HC, Morales MJ, Wang S, Brahmajothi MV, Campbell DL . Voltage-dependent K+ channels. In: Sperelakis N, Kurachi Y, Terzic A, Cohen MV editors; Heart physiology and pathophysiology. San Diego (California): Academic Press; 2001. p 259–80.
Acknowledgements
We thank Dr RASMUSSON (University at Buffalo, SUNY) for the fKv1.4ΔN cDNA.
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Zhang, D., Wang, Sm., Chen, H. et al. Effects of diltiazem and propafenone on the inactivation and recovery kinetics of fKv1.4 channel currents expressed in Xenopus oocytes. Acta Pharmacol Sin 32, 465–477 (2011). https://doi.org/10.1038/aps.2010.234
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DOI: https://doi.org/10.1038/aps.2010.234
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