Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: A potential role of terfenadine

Liu,Baoxin; Li,Shuang; Su,Yang; Xiong,Mengting; Xu,Yawei

doi:10.3892/mmr.2014.2640

Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: A potential role of terfenadine

Authors:
- Baoxin Liu
- Shuang Li
- Yang Su
- Mengting Xiong
- Yawei Xu
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Affiliations: Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
Published online on: October 14, 2014 https://doi.org/10.3892/mmr.2014.2640
Pages: 3217-3226

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Abstract

Terfenadine is a second generation histamine receptor antagonist which is widely used as a non‑sedating antihistamine to relieve allergic responses. However, terfenadine has been associated with a number of side effects on cardiac electrical activities through blocking multiple ion channels in the heart, particularly K+ channels. Previous studies have also implied that terfenadine may have a potential antiarrhythmic effect; however, the electrophysiological influence by which terfenadine exerts its antiarrhythmic action remains elusive. Based on evidence from previous studies, it was hypothesized that the antiarrhythmic effect of terfenadine may be similar to that of amiodarone. The present study aimed to examine the effect of terfenadine on the QTc interval and on experimental ventricular arrhythmia in rats by comparing with that of amiodarone. The effect of terfenadine and amiodarone on the QTc interval was evaluated by comparison of multiple electrocardiograms. Barium chloride/aconitine was intraperitoneally injected to induce ventricular arrhythmias. Normal saline was administered to control rats. In comparison with normal saline, terfenadine and amiodarone similarly dose‑dependently prolonged the QTc interval in rats. In the barium chloride/aconitine-induced ventricular arrhythmia model, terfenadine and amiodarone did not only similarly delay the onset time of arrhythmias induced by barium chloride (all P<0.05), but also increased the cumulative dosage of aconitine required to induce various arrhythmias (all P<0.05). Furthermore, the two drugs equivalently caused a significant decrease in the duration of ventricular tachycardia in comparison with the normal saline controls (all P<0.05). The present study suggested that terfenadine prolonged the QTc interval and decreased ventricular tachycardia duration. The potential protective effect of terfenadine in ventricular arrhythmia may be similar to that of amiodarone.

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1	Ghoneim M, Issa R and Tawfik A: Assay of terfenadine in pharmaceutical formulation and human plasma by adsorptive stripping voltammetry. J Pharm Biomed Anal. 26:593–598. 2001. View Article : Google Scholar : PubMed/NCBI
2	Monahan BP, Ferguson CL, Killeavy ES, et al: Torsades de pointes occurring in association with terfenadine use. JAMA. 264:2788–2790. 1990. View Article : Google Scholar : PubMed/NCBI
3	Smith SJ: Cardiovascular toxicity of antihistamines. Otolaryngol Head Neck Surg. 111:348–354. 1994.PubMed/NCBI
4	Lu HR, Hermans AN and Gallacher DJ: Does terfenadine-induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes? Br J Pharmacol. 166:1490–1502. 2012. View Article : Google Scholar
5	Kamiya K, Niwa R, Morishima M, Honjo H and Sanguinetti MC: Molecular determinants of hERG channel block by terfenadine and cisapride. J Pharmacol Sci. 108:301–307. 2008. View Article : Google Scholar : PubMed/NCBI
6	Testai L, Breschi MC, Martinotti E and Calderone V: QT prolongation in guinea pigs for preliminary screening of torsadogenicity of drugs and drug-candidates. II. J Appl Toxicol. 27:270–275. 2007. View Article : Google Scholar : PubMed/NCBI
7	Iribarren C, Round AD, Peng JA, et al: Validation of a population-based method to assess drug-induced alterations in the QT interval: a self-controlled crossover study. Pharmacoepidemiol Drug Saf. 22:1222–1232. 2013. View Article : Google Scholar : PubMed/NCBI
8	Li XW, Niu SC, Zhang XP, et al: Differences of promethazine and terfenadine on ion channels in guinea pig ventricular myocytes. Chin Med J (Engl). 119:944–947. 2006.PubMed/NCBI
9	Woosley RL, Chen Y, Freiman JP and Gillis RA: Mechanism of the cardiotoxic actions of terfenadine. JAMA. 269:1532–1536. 1993. View Article : Google Scholar : PubMed/NCBI
10	Rajput SK, Singh JN and Sharma SS: Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs. Pharmacol Rep. 62:683–688. 2010. View Article : Google Scholar
11	Aslanian R, Piwinski JJ, Zhu X, et al: Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs. Bioorg Med Chem Lett. 19:5043–5047. 2009. View Article : Google Scholar : PubMed/NCBI
12	Mehta A, Chung Y, Sequiera GL, et al: Pharmacoelectrophysiology of viral-free induced pluripotent stem cell-derived human cardiomyocytes. Toxicol Sci. 131:458–69. 2013. View Article : Google Scholar : PubMed/NCBI
13	Stork D, Timin EN, Berjukow S, et al: State dependent dissociation of HERG channel inhibitors. Br J Pharmacol. 151:1368–76. 2007. View Article : Google Scholar : PubMed/NCBI
14	Davies AJ, Harindra V, McEwan A and Ghose RR: Cardiotoxic effect with convulsions in terfenadine overdose. BMJ. 298:3251989. View Article : Google Scholar : PubMed/NCBI
15	Hess P, Rey M, Wanner D, Steiner B and Clozel M: Measurements of blood pressure and electrocardiogram in conscious freely moving guineapigs: a model for screening QT interval prolongation effects. Lab Anim. 41:470–80. 2007. View Article : Google Scholar : PubMed/NCBI
16	Huang W, Wang Y, Cao YG, et al: Antiarrhythmic effects and ionic mechanisms of allicin on myocardial injury of diabetic rats induced by streptozotocin. Naunyn Schmiedebergs Arch Pharmacol. 386:697–704. 2013. View Article : Google Scholar : PubMed/NCBI
17	Wilhelms M, Rombach C, Scholz EP, Dössel O and Seemann G: Impact of amiodarone and cisapride on simulated human ventricular electrophysiology and electrocardiograms. Europace. 14:v90–v96. 2012. View Article : Google Scholar : PubMed/NCBI
18	Taniguchi T, Uesugi M, Arai T, et al: Chronic probucol treatment decreases the slow component of the delayed-rectifier potassium current in CHO cells transfected with KCNQ1 and KCNE1: a novel mechanism of QT prolongation. J Cardiovasc Pharmacol. 59:377–386. 2012. View Article : Google Scholar
19	Khisatmutdinova RIu, Baschenko NZh, Zarudii FS, et al: Some aspects of the antiarrhythmic effect of glialin. Eksp Klin Farmakol. 69:26–28. 2006.PubMed/NCBI
20	Huang W, Wang Y, Cao YG, et al: Antiarrhythmic effects and ionic mechanisms of allicin on myocardial injury of diabetic rats induced by streptozotocin. Naunyn Schmiedebergs Arch Pharmacol. 386:697–704. 2013. View Article : Google Scholar : PubMed/NCBI
21	Wada K, Nihira M, Hayakawa H, et al: Effects of long-term administrations of aconitine on electrocardiogram and tissue concentrations of aconitine and its metabolites in mice. Forensic Sci Int. 148:21–29. 2005. View Article : Google Scholar : PubMed/NCBI
22	Gao Y, Li P, Ma LX, et al: Effects of acute administration of ethanol on experimental arrhythmia. Chin J Physiol. 55:307–313. 2012.PubMed/NCBI
23	Testai L, Cecchetti V, Sabatini S, et al: Effects of K openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs. J Pharm Pharmacol. 62:924–930. 2010.PubMed/NCBI
24	Zhang YH, Cheng H, Alexeenko VA, Dempsey CE and Hancox JC: Characterization of recombinant hERG K(+) channel inhibition by the active metabolite of amiodarone desethyl-amiodarone. J Electrocardiol. Sep–Oct;43(5): 440–8. 2010. View Article : Google Scholar
25	Coast GM: Intracellular Na⁺, K⁺ and Cl− activities in Acheta domesticus Malpighian tubules and the response to a diuretic kinin neuropeptide. J Exp Biol. 215:2774–2785. 2012.PubMed/NCBI
26	Discala F, Belachgar F, Planelles G, Hulin P and Anagnostopoulos T: Barium- or quinine-induced depolarization activates K⁺, Na⁺ and cationic conductances in frog proximal tubular cells. J Physiol. 448:525–537. 1992. View Article : Google Scholar : PubMed/NCBI
27	Kehl SJ, Fedida D and Wang Z: External Ba(2+) block of Kv4.2 channels is enhanced in the closed-inactivated state. Am J Physiol Cell Physiol. 304:C370–C381. 2013. View Article : Google Scholar : PubMed/NCBI
28	Rowley CN and Roux B: A computational study of barium blockades in the KcsA potassium channel based on multi-ion potential of mean force calculations and free energy perturbation. J Gen Physiol. 142(4): 451–463. 2013. View Article : Google Scholar
29	Kubo Y, Baldwin TJ, Jan YN and Jan LY: Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature. 362:127–33. 1993. View Article : Google Scholar : PubMed/NCBI
30	Ming Z and Nordin C: Terfenadine blocks time-dependent Ca²⁺, Na⁺, and K⁺ channels in guinea pig ventricular myocytes. J Cardiovasc Pharmacol. 26:761–769. 1995. View Article : Google Scholar : PubMed/NCBI
31	Lalevée N, Nargeot J, Barrére-Lemaire S, Gautier P and Richard S: Effects of amiodarone and dronedarone on voltage-dependent sodium current in human cardiomyocytes. J Cardiovasc Electrophysiol. 14:885–90. 2003.PubMed/NCBI
32	Zhou SS, Yang J, Li YQ, et al: Effect of Cl− channel blockers on aconitine-induced arrhythmias in rat heart. Exp Physiol. 90:865–872. 2005.
33	Moreno JD and Clancy CE: Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol. 52:608–19. 2012. View Article : Google Scholar : PubMed/NCBI
34	Goegelein H, Gautier P, Roccon A, O’Connor S and Ruetten H: Effects of the novel amiodarone-like compound SAR114646A on cardiac ion channels and ventricular arrhythmias in rats. Naunyn Schmiedebergs Arch Pharmacol. 384:231–244. 2011. View Article : Google Scholar : PubMed/NCBI
35	Garteiz DA, Hook RH, Walker BJ and Okerholm RA: Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung. 32:1185–1190. 1982.PubMed/NCBI
36	Jones BC, Hyland R, Ackland M, Tyman CA and Smith DA: Interaction of terfenadine and its primary metabolites with cytochrome P450 2D6. Drug Metab Dispos. 26:875–82. 1998.PubMed/NCBI
37	Eckardt L and Breithardt G: Is there a role for amiodarone in the era of the implantable cardioverter-defibrillator? Heart Rhythm. 3:484–487. 2006. View Article : Google Scholar : PubMed/NCBI
38	Echt DS, Liebson PR, Mitchell LB, et al: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial N Engl J Med. 324:781–788. 1991.PubMed/NCBI
39	Naccarelli GV, Wolbrette DL, Samii S, et al: A review of the appropriate and inappropriate use of dronedarone: lessons learned from controlled studies and regulatory submission. J Cardiovasc Pharmacol Ther. 15:24S–30S. 2010.PubMed/NCBI
40	Maseeh-uz-Zaman, Fatima N and Sajjad Z: Amiodarone therapy: don’t forget thyroid. J Pak Med Assoc. 62:268–272. 2012.PubMed/NCBI
41	Garg J, Agrawal N, Marballi A, et al: Amiodarone induced pulmonary toxicity: An unusual response to steroids. Am J Case Rep. 13:62–65. 2012. View Article : Google Scholar : PubMed/NCBI