İskemi Sonrası Verilen Kannabidiol Reperfüzyon ile Uyarılan Aritmilere Karşı Koruyucu Etkilidir

Öz

Amaç: Kannabidiol (KBD) psikolojik etkileri bulunmayan bir bitkisel kannabinoiddir. Klinik uygulamada Huntington hastalığı ve ultipl skleroz tedavisinde kullanılmaktadır. Sıçanlarda koroner arter ligasyonu öncesi verilen KBD’nin reperfüzyon ile uyarılan ventriküler aritmilere karşı koruyucu etkili olduğu bildirilmiştir. Ancak reperfüzyon aritmilerinin klinik tedavisinde kullanılabilmesi için miyokardiyal iskemi sonrasında verildiğinde de etkili olduğu gösterilmelidir. Bu çalışmanın amacı sıçanlarda miyokardiyal iskemi ve reperfüzyon periyotları boyunca infüzyon yolu ile uygulanan KBD tedavisinin reperfüzyon aritmilerine olan etkilerini araştırmaktır. Gereç ve Yöntemler: Miyokardiyal iskemi ve reperfüzyon, anestezi uygulanmış erkek sıçanlarda sırasıyla sol ana koroner arterin 6 dakika ligasyonu ve damar üzerindeki ligatürün 6 dakika açılmasıyla reperfüzyon gerçekleştirildi. Çalışma üç ayrı deney grubunda yürütüldü; (1) Kontrol (n= 6), (2) Lig-KBD (n=6), (3) Rep-KBD (n=6). KBD infüzyon ile sırasıyla Lig-KBD grubunda ligasyon ve Rep-KBD grubunda reperfüzyon periyodu boyunca 9 μg/90 μL/dk/kg dozda intravenöz yolla verildi. Bulgular: Ligasyon boyunca KBD tedavisi ventriküler prematüre kasılma (VPK) süresini kontrol grubuna göre anlamlı azalttı (p=0,024). Reperfüzyonda KBD tedavisi, aritmi skoru, ventriküler taşikardi (VT), ventriküler prematüre kasılma (VPK) ve toplam aritmi sürelerini kontrol grubuna göre azalttı (Toplam aritmi süresi: kontrol; 38,19(6,29-72,44) sn, Lig-KBD; 8,69(0-34,9) sn, Rep-KBD; 1,49(0,14-4,87)sn, p=0,007). Sonuç: Bu çalışmanın sonuçları reperfüzyon periyodu boyunca verilen KBD’nin reperfüzyon ile uyarılan aritmilere karşı güçlü antiaritmik etkiye sahip olduğunu göstermektedir. KBD reperfüzyon aritmilerinin klinik tedavisinde kullanılabilme potansiyeline sahiptir.

Anahtar Kelimeler

• Kannabidiol
• Reperfüzyon aritmileri
• Sıçan
• İnfüzyon

Destekleyen Kurum

Zonguldak Bülent Ecevit Üniversitesi

Proje Numarası

2016-84906727-04

Cannabidiol Given Following the Ischemia Confers Protection Against Reperfusion-Induced Arrhythmia

Öz

Aim: Cannabidiol (CBD) is a non-psychoactive plant cannabinoid. In clinical practice, it has been used in the treatment of Huntington’s disease and multiple sclerosis. CBD given before the coronary ligation has been reported to be protective against reperfusion-induced arrhythmia in rats. However, it should also be demonstrated that is effective against ventricular arrhythmias during ischemia and reperfusion in order to be adapted to the clinical treatment of reperfusion arrhythmias. The aim of this study is to investigate the effects of CBD applied by infusion during both ischemia and reperfusion periods on reperfusion arrhythmias in rats. Material and Methods: Myocardial ischemia and reperfusion were accomplished by the ligation of the left main coronary artery for 6 min and release of the tie on the vessel for 6 min in male anesthetized grurats, respectively. CBD was administered by infusion pump at a dose of 9 μg/90 μL/min/kg during the ligation in Lig-CBD group in Rep-CBD group reperfusion, respectively. Experimental groups of the study were: (1) Control (n = 6), (2) Lig-CBD (n = 6), and (3) Rep-CBD (n = 6). Results: CBD treatment during the ligation significantly decreased the duration of ventricular premature contraction (VPC) compared to the control group (p=0.024). CBD that was given during the reperfusion period significantly decreased the ventricular premature contraction (VPC), ventricular tachycardia (VT) and total length of arrhythmias compared to the control group (total length of arrhythmias: control: 38.19(6.29-72.44) sec, Lig-CBD; 8.69(0-34.9) sec, Rep-CBD; 1.49(0.14-4.87) sec, p=0.007). Conclusion: The results of the study indicate that CBD given during the reperfusion period has a strong antiarrhythmic effect on reperfusioninduced arrhythmia. These results strengthen the potential use of CBD in the clinical treatment of reperfusion arrhythmias.

Anahtar Kelimeler

• Cannabidiol
• Reperfusion arrhythmias
• Rat
• Infusion

Proje Numarası

2016-84906727-04

Kaynakça

1. 1. Bonnemeier H, Wiegand UK, Giannitsis E, Schulenburg S, Hartmann F, Kurowski V, Bode F, Tölg R, Katus HA, Richardt G. Temporal repolarization inhomogeneity and reperfusion arrhythmias in patients undergoing successful primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Impact of admission troponin T. Am Heart J 2003;145(3):484-492.
2. 2. Tatli E, Alicik G, Buturak A, Yilmaztepe M, Aktoz M. Arrhythmias following Revascularization Procedures in the Course of Acute Myocardial Infarction: Are they indicators of reperfusion or ongoing ischemia? Scientific Word Journal 2013;1-7.
3. 3. Majidi M, Kosinski AS, Al-Khatib SM, Smolders L, Cristea E, Lansky AJ, Stone GW, Mehran R, Gibbons RJ, Crijns HJ, Wellens HJ, Gorgels AP, Krucoff MW. Implications of ventricular arrhythmia “bursts” with normal epicardial flow, myocardial blush, and ST-segment recovery in anterior STelevation myocardial infarction reperfusion: A biosignature of direct myocellular injury “downstream of downstream”. Eur Heart J Acute Cardiovasc Care 2015;4(1):51-59.
4. 4. Gonca E, Rapposelli S, Darıcı F, Digiacomo M, Yılmaz Z. Antiarrhythmic activity of a new spiro-cyclic benzopyran activator of the cardiac mitochondrial ATP dependent potassium channels. Arch Pharm Res 2016;39(9):1212-1222.
5. 5. Gonca E. The effects of zileuton and montelukast in reperfusioninduced Arrhythmias in anesthetized rats. Curr Ther Res Clin Exp 2013;75:27-32.
6. 6. Perdicaro DJ, Rodriguez Lanzi C, Fontana AR. Grape pomace reduced reperfusion arrhythmias in rats with a high-fat-fructose diet. Food Funct 2017;8(10):3501-3509.
7. 7. Vajda S, Baczkó I, Leprán I. Selective cardiac plasma membrane K(ATP) channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion. Eur J Pharmacol 2007;577(1-3):115-123.
8. 8. Abdel-Kawy HS. Chronic pantoprazole administration and ischemia--reperfusion arrhythmias in vivo in rats--antiarrhythmic or arrhythmogenic? Cardiovasc Ther 2015;33(2):27-34.

9. 9. Mechoulam R, Peters M, Murillo-Rodriguez E, Honus LO. Cannabidiol-recent advances. Chem Biodivers 2007;4(8):1678- 1692.
10. 10. Lorente Fernández L, Monte Boquet E, Pérez-Miralles F, Gil Gómez I, Escutia Roig M, Boscá Blasco I, Poveda Andrés JL, Casanova-Estruch B. Clinical experiences with cannabinoids in spasticity management in multiple sclerosis. Neurologia 2014;29(5):257-260.
11. 11. Valdeolivas S, Satta V, Pertwee RG, Ferna´ndez-Ruiz J, Sagredo O. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: Role of CB1 and CB2 receptors. ACS Chem Neurosci 2012;3(5):400-406.
12. 12. Peat S. Using cannabinoids in pain and palliative care. Int J Palliat Nurs 2010;16(10):481-485.
13. 13. Naftali T, Bar-Lev SL, Dotan I, Ephraim PL, Fabiana SB, Fred MK. Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled study. Clin Gastroenterol Hepatol 2013;11(10):1276-1280.
14. 14. Stanley CP, Hind WH, O’Sullivan SE. Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol 2013;75(2):313-322.
15. 15. Bisogno T, Hanus L, De Petrocellis L. Molecular targets for cannabidiol and its synthetic analogues: Effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001;134(4):845-852.
16. 16. Ryberg E, Larsson N, Sjo¨gren S. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007;152(7):1092-1101.
17. 17. Zhong B, Wang DH. Protease-activated receptor 2-mediated protection of myocardial ischemia–reperfusion injury: Role of transient receptor potential vanilloid receptors. Am J Physiol Regul Integr Comp Physiol 2009;297(6):1681-1690.
18. 18. Erdem S, Gonca E. Kannabinoid reseptör antagonistleri AM251 ve AM630’un anestezi altındaki sıçanlarda iskemi/reperfüzyon ile uyarılan aritmiler üzerine etkileri. Türkiye Diyabet ve Obezite Dergisi 2018;2(1):35-42.
19. 19. Gonca E, Darıcı F. The effect of cannabidiol on ischaemia/ reperfusion-induced ventricular arrhythmias: The role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 2015;20(1):76-83.
20. 20. Walsh SK, Hepburn CY, Kane KA,Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemiainduced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br J Pharmacol 2010;160(5):1234-1242.
21. 21. Lepran I, Koltai M, Siegmund W, Szekeres L. Coronary artery ligation, early arrhythmias, and determination of the ischemic area in conscious rats. J Pharmacol Methods 1983;9(3):219- 230.
22. 22. Walker MJ, Curtis MJ, Hearse DJ. The Lambeth Conventions: Guidelines for the study of arrhythmias in ischemia infarction and reperfusion. Cardiovasc Res 1988;22(7):447-455.
23. 23. Otani N, Matsuda R, Oda K, Nishino S, Inoue T, Kaneko N. Protective effect of K201 on isoproterenol-induced and ischemic–reperfusion-induced ventricular arrhythmias in the rat: Comparison with diltiazem. J Cardiovasc Pharmacol Ther 2013;18(2):184-190.
24. 24. Ek RO, Yildiz Y, Cecen S, Yenisey C, Kavak T. Effects of tamoxifen on myocardial ischemia–reperfusion ijury model in ovariectomized rats. Mol Cell Biochem 2008;308(1-2):227-235.
25. 25. Gonca E, Bozdogan O. Both mitochondrial KATP channel opening and sarcolemmal KATP channel blockage confer protection against ischemia/reperfusion induced arrhythmia in anesthetized male rats. J Cardiovasc Pharmacol Ther 2010;15(4):403-411.
26. 26. Durst R, Danenberg H, Gallily R. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol 2007;293(6):3602-3607.
27. 27. Rajan TS, Giacoppo S, Iori S. Anti-inflammatory and antioxidant effect of a combination of cannabidiol and moringin in LPSstimulated macrophages. Fitoterapia 2016;112:104-115.
28. 28. Gonca E, Kurt Ç. Cardioprotective effect of Thymoquinone: A constituent of Nigella sativa L. against mycardial ischemia/ reperfusion injury and ventricular arrhythmias in anaesthetized rats. Pak J Pharm Sci 2015;28(4):1267-1273.
29. 29. Tada H, Kutsumi Y,Misawa T. Effects of pretreatment with 2-O-octadecylascorbic acid, a novel free radical scavenger, on reperfusion-induced arrhythmias in isolated perfused rad hearts. J Cardiovasc Pharmacol 1990;16(6):984-991.
30. 30. Diez ER, Renna NF, Prado NJ. Melatonin, given at the time of reperfusion, prevents ventricular arrhythmias in isolated hearts from fructose-fed rats and spontane ously hypertensive rats. J Pineal Res. 2013;55(2):166-173.
31. 31. Sedlis SP. Mechanisms of ventricular arrhyyhmias in acute ischemia and reperfusion. Cardiovasc Clin 1992;(1):3-18.
32. 32. Brown DI, Griendling KK. Regulation of signal transduction by reactive oxygen species in the cardiovascular system . Circ Res 2015;116(3):531-549.
33. 33. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: A therapeutic target. J Clin Invest 2013;123(1):92-100.