Kannabinoid Reseptör Antagonistleri AM251 ve AM630’un Anestezi Altındaki Sıçanlarda İskemi/Reperfüzyon ile Uyarılan Aritmiler Üzerine Etkileri

Amaç: Bu çalışmanın amacı AM251(kannabinoid-1 reseptör antagonisti) ve AM630’un (kannabinoid-2 reseptör antagonisti) anestezi altındaki sıçanlarda iskemi/reperfüzyon (I/R) ile uyarılan aritmiler üzerine etkilerini araştırmaktır. Gereç ve Yöntemler: Wistar Albino türü erkek sıçanlar 3 gruba ayrıldı: I) Kontrol (n=13), II) AM251 (n=17) ve III) AM630 (n=17). AM251 ve AM630 1mg/kg dozda intravenöz yolla ligasyondan 10 dakika önce verildi. Üretan ile anestezi edilen sıçanlarda sol ana koroner arter bağlanarak 6 dakika iskemi, tıkanan damar gevşetilerek 10 dakika reperfüzyon yapıldı. Tüm gruplardaki deneklerde iskemi ve reperfüzyon periyotlarında ventriküler aritmi süreleri, EKG’de QRS, Q-T ve P-R aralıkları, kalp atımı ve ortalama arteriyal kan basıncı hesaplandı. Bulgular: AM251 reperfüzyon periyodunda ölüm oranını, ventriküler taşikardi ve ventriküler fibrilasyonun görülme sıklığını, ventriküler fibrilasyon süresi, toplam aritmi süresi ve aritmi skorunu kontrol grubuna göre istatistiksel olarak anlamlı bir şekilde artırdı (p<0.05). Sonuç: Kannabinoid-1 reseptör antagonisti AM251 I/R ile uyarılan aritmileri arttırdı. Kannabinoid-2 reseptör antagonisti AM630 ise herhangi bir etki göstermedi. Bu sonuçlar endojen kannabinoidlerin KB1 reseptör aktivasyonu yoluyla ventriküler aritmilerin oluşumunu azaltıcı bir role sahip olabileceğini göstermektedir.

Anahtar Kelimeler:

AM251, AM630, Kannabinoidler, İskemi/reperfüzyon aritmileri

The Effects of Cannabinoid Receptor Antagonists AM251 and AM630 on Ischemia/Reperfusion-Induced Arrhythmias in Anesthetized Rats

Aim: The aim of this study is to investigate the effects of AM251 (cannabinoid-1 receptor antagonist) and AM630 (cannabinoid-2 receptor antagonist) on ischemia/reperfusion (I/R)-induced arrhythmias in anesthetized rats. Materials and Methods: Wistar Albino male rats were divided into 3 groups: I) Control (n = 13), II) AM251 (n = 17) and III) AM630 (n = 17). AM251 and AM630 were administered intravenously at 1 mg / kg dose 10 minutes prior to ligation. In the anesthetized rats with urethan, the left main coronary artery was ligated to perform the ischemia for 6 minutes, the occluded artery was loosened and reperfusion was performed for 10 minutes.Ventricular arrhythmia durations, QRS, Q-T and P-R intervals in ECG recordings, heart rate and mean arterial blood pressure were calculated in ischemia and reperfusion period in all in all groups of rats. Results: The AM251 significantly increased mortality, the incidence of ventricular tachycardia and ventricular fibrillation, the duration of total arrhythmia and the ventricular fibrillation and the arrhythmia scores compared to the control group (p<0.05). Conclusion: The cannabinoid-1 receptor antagonist AM251 increased I/R-induced arrhythmias. The cannabinoid-2 receptor antagonist AM630 did not show any effect. These results demonstrate that endogenous cannabinoids may have a role in the reducing the generatiom of ventricular arrhythmias via KB1 receptor activation.

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1. Ferrari R, et al. Reperfusion damage- a story of success, failure, and hope. Circ J. 2017;81(2):131-141.
2. Gonca E, et al. Cardioprotective effect of zileuton: A 5-lipoxygenase inhibitor against myocardial ischemia/ reperfusion injury. Turkish Journal of Thoracic and Cardiovascular Surgery. 2017;25(2):273-281.
3. Gonca E. The effects of zileuton and montelukast in reperfusion-induced arrhythmias in anesthetized rats. Curr Ther Res Clin Exp. 2013;75:27-32.
4. Howlett AC, et al. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47:345–358.
5. Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol. 2006;105(1-2):1-25.
6. Bisogno T, et al. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. British Journal of Pharmacology. 2001;134(4):845-852.
7. Gebremedhin D, et al. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+channel current. The American Journal Physiology. 1999;276:2085- 2093.
8. Liu J, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells. The Biochemical Journal. 2000;346:835-840.
9. Di Marzo V. The endocannabinoid system: Its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacological Research. 2009;60(2):77-84.
10. Walsh SK, et al. Pharmacological proﬁling of the hemodynamic effects of cannabinoid ligands: A combined in vitro and in vivo approac. Pharmacol Research Perspect. 2015;3(3):1-17.
11. Cunha P, et al. Endocannabinoid system in cardiovascular disorders - new pharmacotherapeutic opportunities. Journal of Pharmacy& Bioallied Science. 2011;3(3):350-360.
12. Wagner JA, et al. CB(1) cannabinoid receptor antagonism promotes remodelling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction. British Journal Pharmacology. 2003;138:1251-1258.
13. Batkai S, et al. Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors. American Journal of Physiology. Heart and Circulatory Physiology. 2004;287(2):595–600.
14. Hepburn CY, et al. Cannabidiol as an antiarrhythmic, the role of the CB1 receptors. Heart. 2011;97(24):8.
15. Andrag E, Curtis MJ. Feasibility of targeting ischemia-related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids. British Journal of Pharmacology. 2013;169(8):1840-1848.
16. Hajrasouliha AR, et al. Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. European Journal of Pharmacology. 2007;579: 246-252.
17. Hosohata K, et al. AM630 is a competitive cannabinoid receptor antagonist in the guinea pig brain. Life Sciences. 1997;61(9):115-118.
18. Lan R, et al. Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. Journal of Medicinal Chemistry. 1999;42:769-776.
19. Curtis MJ, et al. The Lambeth Conventions (II): Guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacology&Therapeutics. 2013;139(2):213- 248.
20. Lepran I, et al. Coronary artery ligation, early arrhythmias, and determination of the ischemic area in conscious rats. Journal Pharmacological Methods. 1983;9(3):219-230.
21. Bazett HC. An analysis of the time relationships of electrocardiograms. Annals of Noninvasive Electrocardiology. 2006;2(2):177-194.
22. Gulcu-Bulut N, et al. Pretreatment with stellate ganglion blockade before ischemia reduces infarct size in rat hearts. Saudi Medical Journal. 2010;31(2):148-152.
23. Rudz R, et al. Acute myocardial infarction inhibits the neurogenic tachycardic and vasopressor response in rats via presynaptic cannabinoid type 1 receptor. Journal Pharmacol Experimental Therapeutics. 2012;343:198-205.
24. Faber GM, Rudy Y. Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: A simulation study of cellular mechanism. Cardiovasc Research. 2007;75(1):79-88.
25. Oka S, et al. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 2007;362:928-934.
26. Robertson-Gray OJ, et al. Exogenous lysophosphatidolinositol exacerbates myocardial tissue ınjury via a GPR55 dependent mechanism. Heart. 2014;100(4).
27. Ryberg E, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology. 2007;152(7):1092-2101.
28. Kalogeris T, et al. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol. 2012;298:229-317.
29. Pogwizd SM, Corr PB. Electrophysiologic mechanisms underlying arrhythmias due to reperfusion of ischemic myocardium. Circulation. 1987;76(2):404-426.
30. Gonca E, Darici F. The effect of cannabidiol on ischemia/ reperfusion-induced ventricular arrhythmias: The role of adenosine A1 receptors. Journal of Cardiovascular Pharmacology and Therapeutics. 2014;20(1):76-83.
31. Krylatov AV, et al. Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion. Bulletin of Experimental Biology and Medicine. 2001;131(6):523-525.
32. Lepicier P, et al. Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts. Life Science. 2007;81:1373-1380.
33. Qian Li, et al. Electrophysiological effects of anandamide on rat myocardium. Brithis Journal Pharmacology. 2009;158(8):2022–2029.
34. Farkas A, et al. Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart. Br J Pharmacol. 1999;128(1):41-50.
35. Rees SA, Curtis MJ. Pharmacological analysis in rat of the role of the ATP-sensitive potassium channel as a potential target for antifibrillatory intervention in acute myocardial ischaemia. J Cardiovasc Pharmacol. 1995;26:280-288.
36. Rees SA, Curtis MJ. Which cardiac potassium channel subtype is the preferable target for suppression of ventricular arrhythmias? Pharmacol Ther. 1996;69:199-217.
37. Tamargo J, et al. Pharmacology of cardiac potassium channels. Cardiovasc Research. 2004;62(1):9-33.
38. Tsuchihashi K, Curtis MJ. Influence of tedisamil on the initiation and maintenance of ventricular fibrillation: Chemical defibrillation by Ito blockade? J Cardiovasc Pharmacol. 1991;18:445-456.
39. Wagner JA, et al. Hemodynamic effects of cannabinoids: Coronary and cerebral vasodilatation mediated by cannabinoid CB1 receptors. European Journal Pharmacol. 2001;423:203- 210.
40. Pacher P, et al. Blood pressure regulation by endocannabinoids and their receptors. Neuropharmacology. 2005;48(8):1130- 1138.