Nil HOCAOĞLU, Yeşim TUNÇOK, Şule KALKAN, Kubilay ORANSAY, Müjgan BÜYÜKDELİGÖZ

The Effects of the Adenosine Receptor Antagonists on the Reverse of Cardiovascular Toxic Effects Induced by Citalopram In-Vivo Rat Model of Poisoning

Background: Citalopram is a selective serotonin re- uptake inhibitor that requires routine cardiac monitoring to prevent a toxic dose. Prolongation of the QTinterval has been observed in acute citalopram poisoning. Our previous experimental study showed that citalopram may be lead to QT prolongation by stimulatingadenosine A1 receptors without affecting the release ofadenosine. Aims: We examined the effects of adenosine receptorantagonists in reversing the cardiovascular toxic effectsinduced by citalopram in rats. Study Design: Animal experimentation. Methods: Rats were divided into three groups ran- domly (n=7 for each group). Sodium cromoglycate (20mg/kg) was administered to all rats to inhibit adenosineA3 receptor mast cell activation. Citalopram toxicitywas achieved by citalopram infusion (4 mg/kg/min) for20 minutes. After citalopram infusion, in the controlgroup (Group 1), rats were given an infusion of dextrose solution for 60 minutes. In treatment groups, theselective adenosine A1 antagonist DPCPX (Group 2,8-cyclopentyl-1,3-dipropylxanthine, 20 μg/kg/min) orthe selective A2a antagonist CSC (Group 3, 8-(3-chlo- rostyryl)caffeine, 24 μg/kg/min) was infused for 60 minutes. Mean arterial pressure (MAP), heart rate(HR), QRS duration and QT interval measurementswere followed during the experiment period. Statistical analysis was performed by ANOVA followed byTukey s multiple comparison tests.Results: Citalopram infusion reduced MAP and HRand prolonged the QT interval. It did not cause anysignificant difference in QRS duration in any group.When compared to the control group, DPCPX aftercitalopram infusion shortened the prolongation of theQT interval after 40, 50 and 60 minutes (p

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1. DRUGDEX®System: Klasco RK (Ed): DRUGDEX® System. Truven Health Analytics, Greenwood Village, Colorado, Vol. 162 expires 12/2014.
2. Cooke MJ, Waring WS. Citalopram and cardiac toxicity. Eur J Clin Pharmacol 2013;69:755-60. [CrossRef]
3. Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA, et. al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry 2014;75:441-9. [CrossRef]
4. Kogut C, Crouse EB, Vieweg WV, Hasnain M, Baranchuk A, Digby GC, et.al. Selective serotonin reuptake inhibitors and torsade de pointes: new concepts and new directions derived from a systematic review of case reports. Ther Adv Drug Saf 2013;4:189-98. [CrossRef]
5. Liotier J, Coudoré F. Drug monitoring of a case of citalopram overdosage. Drug Chem Toxicol 2011;34:420-3. [CrossRef]
6. Jimmink A, Caminada K, Hunfeld NG, Touw DJ. Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs, overview of 26 cases. Ther Drug Monit 2008;30:365-71. [CrossRef]
7. Tarabar AF, Hoffman RS, Lelson LS. Citalopram overdose, late presentation if torsdae de pointes with cardiac arrest. J Med Toxicol 2008;4:101-5. [CrossRef]
8. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 2004;42:277-85. [CrossRef]
9. Lynge J, Hellsten Y. Distribution of adenosine A1, A2A and A2B receptors in human skeletal muscle. Acta Physiol Scand 2000;169:283-90. [CrossRef]
10. Yan L, Burbiel JC, Maas A, Muller CE. Adenosine receptor ago- nists: from basic medicinal chemistry to clinical development. Expert Opin Emerg Drugs 2003;8:537-76. [CrossRef]
11. Olsson RA, Pearson JD. Cardiovascular purinoceptors. Physiol Rev 1990;70:761-45.
12. Belardinelli L, Shryock JC, Snowdy S, Zhang Y, Monopoli A, Lozza G, et al. The A2a adenosine receptor mediates coronary vasodilation. J Pharmacol Exp Ther 1998;284:1066-73.
13. Pousti A, Deemyad T, Malihi G. Mechanism of inhibitory effect of citalopram on isolated guinea-pig atria in relation to adenosine receptor. Hum Psychopharmacol 2004;19:347-50. [CrossRef]
14. Oransay K, Hocaoglu N, Buyukdeligoz M, Tuncok Y, Kalkan S. The role of adenosine receptors and endogenous adenosine in citalopram-induced cardiovascular toxicity. Indian J Pharmacol 2014;46:378-85. [CrossRef]
15. Kalkan S, Aygoren O, Akgun A, Gidener S, Guven H, Tuncok Y. Do adenosine receptors play a role in amitriptyline-induced car- diovascular toxicity in rats. J Toxicol Clin Toxicol 2004;42:945- 54. [CrossRef]
16. Kobayashi T, Washiyama K, Ikeda K. Inhibition of G protein- activated inwardly rectifying K+ channels by various antide- pressant drugs. Neuropsychopharmacology 2004;29:1841-51. [CrossRef]
17. Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP. Human ether-a- go-go related gene (hERG) K+ channels: function and dysfunc- tion. Prog Biophys Mol Biol 2008;98:137-48. [CrossRef]
18. Jo SH1, Youm JB, Lee CO, Earm YE, Ho WK. Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol 2000;129:1474-80. [CrossRef]
19. Pacher P, Kecskemeti V. Cardiovascular Side Effects of New Antidepressants and Antipsychotics: New Drugs, old Concerns? Curr Pharm Des 2004;10:2463-75. [CrossRef]
20. Witchel HJ1, Pabbathi VK, Hofmann G, Paul AA, Hancox JC. Inhibitor actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents. FEBS Lett 2002;512:59-66. [CrossRef]
21. Gintant G. An evaluation of hERG current assay performance, Translating preclinical safety studies to clinical QT prolonga- tion. Pharmacol Ther 2011;129:109-19. [CrossRef]
22. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M. Ionic basis of electrophysiological actions of adenosine on cardiomyocytes. FASEB J 1995;9:359-65.
23. Lerman BB, Belardinelli L. Cardiac electrophysiology of adenosine. Basic and clinical concepts. Circulation 1991;83:1499- 509. [CrossRef]
24. Shen WK, Kurachi Y. Mechanisms of adenosine-mediated actions on cellular and clinical cardiac electrophysiology. Mayo Clin Proc 1995;70:274-91.[CrossRef]