Abstract
Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active S-enantiomer of the racemic mixture of RS-citalopram and is widely used in the treatment of depression. The effects of escitalopram and citalopram on the human ether-a-go-go-related gene (hERG) channels expressed in human embryonic kidney cells were investigated using voltage-clamp and Western blot analyses. Both drugs blocked hERG currents in a concentration-dependent manner with an IC50 value of 2.6 μM for escitalopram and an IC50 value of 3.2 μM for citalopram. The blocking of hERG by escitalopram was voltage-dependent, with a steep increase across the voltage range of channel activation. However, voltage independence was observed over the full range of activation. The blocking by escitalopram was frequency dependent. A rapid application of escitalopram induced a rapid and reversible blocking of the tail current of hERG. The extent of the blocking by escitalopram during the depolarizing pulse was less than that during the repolarizing pulse, suggesting that escitalopram has a high affinity for the open state of the hERG channel, with a relatively lower affinity for the inactivated state. Both escitalopram and citalopram produced a reduction of hERG channel protein trafficking to the plasma membrane but did not affect the short-term internalization of the hERG channel. These results suggest that escitalopram blocked hERG currents at a supratherapeutic concentration and that it did so by preferentially binding to both the open and the inactivated states of the channels and by inhibiting the trafficking of hERG channel protein to the plasma membrane.
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Baranchuk A, Simpson CS, Methot M, Gibson K, Strum D (2008) Corrected QT interval prolongation after an overdose of escitalopram, morphine, oxycodone, zopiclone and benzodiazepines. Can J Cardiol 24:e38–e40
Brendel J, Peukert S (2003) Blockers of the Kv1.5 channel for the treatment of atrial arrhythmias. Curr Med Chem Cardiovasc Hematol Agents 1:273–287
Bril A, Gout B, Bonhomme M, Landais L, Faivre JF, Linee P, Poyser RH, Ruffolo RR Jr (1996) Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872. J Pharmacol Exp Ther 276:637–646
Catalano G, Catalano MC, Epstein MA, Tsambiras PE (2001) QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol 24:158–162
Choi JS, Choi BH, Ahn HS, Kim MJ, Rhie DJ, Yoon SH, do Min S, Jo YH, Kim MS, Sung KW, Hahn SJ (2003) Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells. Biochem Pharmacol 66:2125–2132
Dennis AT, Nassal D, Deschenes I, Thomas D, Ficker E (2011) Antidepressant-induced ubiquitination and degradation of the cardiac potassium channel hERG. J Biol Chem 286:34413–34425
Engebretsen KM, Harris CR, Wood JE (2003) Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med 25:163–166
Fayssoil A, Issi J, Guerbaa M, Raynaud JC, Heroguelle V (2011) Torsade de Pointes induced by citalopram and amiodarone. Ann Cardiol Angeiol (Paris) 60:165–168
Ganapathi SB, Kester M, Elmslie KS (2009) State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy. Am J Physiol Cell Physiol 296:C701–C710
Garnock-Jones KP, McCormack PL (2010) Escitalopram: a review of its use in the management of major depressive disorder in adults. CNS Drugs 24:769–796
Hyttel J (1982) Citalopram—pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuropsychopharmacol Biol Psychiatry 6:277–295
Kass RS, Cabo C (2000) Channel structure and drug-induced cardiac arrhythmias. Proc Natl Acad Sci U S A 97:11683–11684
Keller MB (2000) Citalopram therapy for depression: a review of 10 years of European experience and data from U.S. clinical trials. J Clin Psychiatry 61:896–908
Kikuchi K, Nagatomo T, Abe H, Kawakami K, Duff HJ, Makielski JC, January CT, Nakashima Y (2005) Blockade of HERG cardiac K+ current by antifungal drug miconazole. Br J Pharmacol 144:840–848
Lee HM, Hahn SJ, Choi BH (2010) Open channel block of Kv1.5 currents by citalopram. Acta Pharmacol Sin 31:429–435
Melzacka M, Rurak A, Adamus A, Daniel W (1984) Distribution of citalopram in the blood serum and in the central nervous system of rats after single and multiple dosage. Pol J Pharmacol Pharm 36:675–682
Milnes JT, Crociani O, Arcangeli A, Hancox JC, Witchel HJ (2003) Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. Br J Pharmacol 139:887–898
Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC (2000) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A 97:12329–12333
Pacher P, Bagi Z, Lako-Futo Z, Ungvari Z, Nanasi PP, Kecskemeti V (2000) Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle comparison with clomipramine. Gen Pharmacol 34:17–23
Pacher P, Kecskemeti V (2004) Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 10:2463–2475
Parker NG, Brown CS (2000) Citalopram in the treatment of depression. Ann Pharmacother 34:761–771
Paul AA, Witchel HJ, Hancox JC (2002) Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine. Br J Pharmacol 136:717–729
Perchenet L, Hilfiger L, Mizrahi J, Clement-Chomienne O (2001) Effects of anorexinogen agents on cloned voltage-gated K+ channel hKv1.5. J Pharmacol Exp Ther 298:1108–1119
Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson CL, Holzem KM, Delisle BP, Anson BD, Makielski JC, January CT (2006) Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. Br J Pharmacol 149:481–489
Sanchez C (2006) The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol 99:91–95
Thomas D, Gut B, Wendt-Nordahl G, Kiehn J (2002) The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 300:543–548
Tseng PT, Lee Y, Lin YE, Lin PY (2012) Low-dose escitalopram for 2 days associated with corrected QT interval prolongation in a middle-aged woman: a case report and literature review. Gen Hosp Psychiatry 34(210):e213–e215
Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP (2012) hERG K+ channels: structure, function, and clinical significance. Physiol Rev 92:1393–1478
Vandenberg JI, Walker BD, Campbell TJ (2001) HERG K+ channels: friend and foe. Trends Pharmacol Sci 22:240–246
Waugh J, Goa KL (2003) Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 17:343–362
Witchel HJ, Pabbathi VK, Hofmann G, Paul AA, Hancox JC (2002) Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents. FEBS Lett 512:59–66
Yang MJ, Sim S, Jeon JH, Jeong E, Kim HC, Park YJ, Kim IB (2013) Mitral and tufted cells are potential cellular targets of nitration in the olfactory bulb of aged mice. PLoS One 8:e59673
Zahradnik I, Minarovic I, Zahradnikova A (2008) Inhibition of the cardiac L-type calcium channel current by antidepressant drugs. J Pharmacol Exp Ther 324:977–984
Acknowledgments
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (2012R1A1A2008274) and by the Research Fund 2012 of The Catholic University of Korea (J.S. Choi).
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Chae, Y.J., Jeon, J.H., Lee, H.J. et al. Escitalopram block of hERG potassium channels. Naunyn-Schmiedeberg's Arch Pharmacol 387, 23–32 (2014). https://doi.org/10.1007/s00210-013-0911-y
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DOI: https://doi.org/10.1007/s00210-013-0911-y