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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

Zacopride Exerts an Antiarrhythmic Effect by Specifically Stimulating the Cardiac Inward Rectifier Potassium Current in Rabbits: Exploration of a New Antiarrhythmic Strategy

Author(s): Yuanyuan Lin, Junhu Li, Baozhong Zhu, Qinghua Liu, Xiaojie Bai, Bingmei Chang, Yanlin Guo, Qilong Feng*, Xuewen Li*, Bowei Wu and Jimin Cao

Volume 26, Issue 44, 2020

Page: [5746 - 5754] Pages: 9

DOI: 10.2174/1381612826666200701135508

Price: $65


Background: Zacopride, a potent antagonist of 5-HT3 receptors and an agonist of 5-HT4 receptors, is a gastrointestinal prokinetic agent. In a previous study, we discovered that zacopride selectively stimulated the inward rectifier potassium current (IK1) in the rat and that agonizing IK1 prevented or eliminated aconitine-induced arrhythmias in rats.

Objective: Our aims were to confirm that the antiarrhythmic effects of zacopride are mediated by selectively enhancing IK1 in rabbits.

Methods: The effects of zacopride on the function of the main ion channels were investigated using a whole-cell patch-clamp technique in rabbits. Effects of zacopride on cardiac arrhythmias were also explored experimentally both in vivo and in vitro.

Results: Zacopride moderately enhanced cardiac IK1 but had no apparent action on voltage-gated sodium current (INa), L- type calcium current (ICa-L), sodium-calcium exchange current (INa/Ca), transient outward potassium current (Ito), or delayed rectifier potassium current (IK) in rabbits. Zacopride also had a marked antiarrhythmic effect in vivo and in vitro. We proved that the resting membrane potential (RMP) was hyperpolarized in the presence of 1 μmol/L zacopride, and the action potential duration (APD) at 90% repolarization (APD90) was shortened by zacopride (0.1-10 μmol/L) in a concentration- dependent manner. Furthermore, zacopride at 1 μmol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes.

Conclusion: Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.

Keywords: Zacopride, inward rectifier potassium current, rabbits, cardiomyocyte, arrhythmias, whole-cell patch-clamp, hyperpolarized.

Janse MJ. Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 2004; 61(2): 208-17.
[] [PMID: 14736537]
Fauconnier J, Lacampagne A, Rauzier JM, Vassort G, Richard S. Ca2+-dependent reduction of IK1 in rat ventricular cells: a novel paradigm for arrhythmia in heart failure? Cardiovasc Res 2005; 68(2): 204-12.
[] [PMID: 16083867]
Li G-R, Lau C-P, Leung T-K, Nattel S. Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles. Heart Rhythm 2004; 1(4): 460-8.
[] [PMID: 15851200]
Sridhar A, Dech SJ, Lacombe VA, et al. Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats. Am J Physiol Heart Circ Physiol 2006; 291(5): H2192-8.
[] [PMID: 16766638]
Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res 2001; 88(11): 1159-67.
[] [PMID: 11397782]
Li G-R, Lau C-P, Ducharme A, Tardif J-C, Nattel S. Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am J Physiol Heart Circ Physiol 2002; 283(3): H1031-41.
[] [PMID: 12181133]
Aimond F, Alvarez JL, Rauzier JM, Lorente P, Vassort G. Ionic basis of ventricular arrhythmias in remodeled rat heart during long-term myocardial infarction. Cardiovasc Res 1999; 42(2): 402-15.
[] [PMID: 10533576]
Pinto JM, Boyden PA. Reduced inward rectifying and increased E-4031-sensitive K+ current density in arrhythmogenic subendocardial purkinje myocytes from the infarcted heart. J Cardiovasc Electrophysiol 1998; 9(3): 299-311.
[] [PMID: 9554735]
Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001; 105(4): 511-9.
[] [PMID: 11371347]
Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 2002; 110(3): 381-8.
[] [PMID: 12163457]
McLerie M, Lopatin AN. Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol 2003; 35(4): 367-78.
[] [PMID: 12689816]
Domenighetti AA, Boixel C, Cefai D, Abriel H, Pedrazzini T. Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation. J Mol Cell Cardiol 2007; 42(1): 63-70.
[] [PMID: 17070838]
Miake J, Marbán E, Nuss HB. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest 2003; 111(10): 1529-36.
[] [PMID: 12750402]
Sung RJ, Wu S-N, Wu J-S, Chang H-D, Luo C-H. Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study. Am J Physiol Heart Circ Physiol 2006; 291(6): H2597-605.
[] [PMID: 16877549]
Seemann G, Sachse FB, Weiss DL, Ptácek LJ, Tristani-Firouzi M. Modeling of IK1 mutations in human left ventricular myocytes and tissue. Am J Physiol Heart Circ Physiol 2007; 292(1): H549-59.
[] [PMID: 16936001]
Apkon M, Nerbonne JM. Characterization of two distinct depolarization-activated K+ currents in isolated adult rat ventricular myocytes. J Gen Physiol 1991; 97(5): 973-1011.
[] [PMID: 1865177]
Boyle WA, Nerbonne JM. Two functionally distinct 4-aminopyridine-sensitive outward K+ currents in rat atrial myocytes. J Gen Physiol 1992; 100(6): 1041-67.
[] [PMID: 1484284]
Pond a L, Scheve BK, Benedict a T, Petrecca K, Van Wagoner DR, Shrier a. Expression of distinct ERG proteins in rat, mouse, and human heart. Relation to functional I(Kr) channels. J Biol Chem 2000; 275: 5997-6006.
Shibasaki T. Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol 1987; 387: 227-50.
[] [PMID: 2443680]
Veldkamp MW, van Ginneken ACG, Bouman LN. Single delayed rectifier channels in the membrane of rabbit ventricular myocytes. Circ Res 1993; 72(4): 865-78.
[] [PMID: 8443873]
Thomas D, Karle CA, Kiehn J. The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications. Curr Pharm Des 2006; 12(18): 2271-83.
[] [PMID: 16787254]
Baczkó I, Jost N, Virág L, Bősze Z, Varró A. Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve. Prog Biophys Mol Biol 2016; 121(2): 157-68.
[] [PMID: 27208697]
Gaborit N, Le Bouter S, Szuts V, et al. Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol 2007; 582(Pt 2): 675-93.
[] [PMID: 17478540]
Zobel C, Cho HC, Nguyen TT, et al. Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2. J Physiol 2003; 550(Pt 2): 365-72.
[] [PMID: 12794173]
Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ. Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol 1988; 40(4): 302-5.
[] [PMID: 2900320]
Yamakuni H, Nakayama H, Matsui S, Imazumi K, Matsuo M, Mutoh S. Inhibitory effect of zacopride on Cisplatin-induced delayed emesis in ferrets. J Pharmacol Sci 2006; 101(1): 99-102.
[] [PMID: 16651699]
Meyer LCR, Fuller A, Mitchell D. Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats. Am J Physiol Regul Integr Comp Physiol 2006; 290(2): R405-13.
[] [PMID: 16166206]
Xu J, Zaim S, Pelleg A. Effects of pinacidil, verapamil, and heart rate on afterdepolarizations in the guinea-pig heart in vivo. Heart Vessels 1996; 11(6): 289-302.
[] [PMID: 9248848]
Wang LH, Yu CH, Fu Y, Li Q, Sun YQ. Berberine elicits anti-arrhythmic effects via IK1/Kir2.1 in the rat type 2 diabetic myocardial infarction model. Phytother Res 2011; 25(1): 33-7.
[] [PMID: 20623609]
Gómez R, Caballero R, Barana A, et al. Nitric oxide increases cardiac IK1 by nitrosylation of cysteine 76 of Kir2.1 channels. Circ Res 2009; 105(4): 383-92.
[] [PMID: 19608980]
Xiao GS, Zhou JJ, Wang GY, Cao CM, Li GR, Wong TM. In vitro electrophysiologic effects of morphine in rabbit ventricular myocytes. Anesthesiology 2005; 103(2): 280-6.
[] [PMID: 16052110]
Caballero R, Dolz-Gaitón P, Gómez R, et al. Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. Proc Natl Acad Sci USA 2010; 107(35): 15631-6.
[] [PMID: 20713726]
Piao L, Li J, McLerie M, Lopatin AN. Transgenic upregulation of IK1 in the mouse heart is proarrhythmic. Basic Res Cardiol 2007; 102(5): 416-28.
[] [PMID: 17546530]
Wu BW, Cao JM. On the risk concerns of zacopride, a moderate IK1 channel agonist with cardiac protective action. J Cardiovasc Pharmacol 2014; 64(4): 357-9.
[] [PMID: 25072868]
Liu QH, Li XL, Xu YW, Lin YY, Cao JM, Wu BW. A novel discovery of IK1 channel agonist: zacopride selectively enhances IK1 current and suppresses triggered arrhythmias in the rat. J Cardiovasc Pharmacol 2012; 59(1): 37-48.
[] [PMID: 21921806]
Zhai XW, Zhang L, Guo YF, et al. The IK1/Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the rat. PLoS One 2017; 12(5) : e0177600.
[] [PMID: 28542320]
Zobel C1. Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2. J Physiol 2003; 15(550): 365-72.

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