5-Lipoksigenaz inhibitörü zileutonun miyokardiyal iskemi/reperfüzyon hasarına karşı kalp koruyucu etkisi

Amaç: Bu çalışmada zileuton’un miyokardiyal iskemi/ reperfüzyon hasarı ve iskemi ile uyarılan ventriküler aritmiler üzerine olan etkileri değerlendirildi ve 5-lipoksigenaz yolağının miyokardiyal iskemi/reperfüzyon hasarının patofizyolojisindeki rolü araştırıldı. Çalışma planı: Anestezi altındaki sıçanlarda, miyokardiyal iskemi 120 dakikalık reperfüzyon periyodundan önce sol ana koroner arterin 30 dakikalık ligasyonu ile oluşturuldu. Zileuton 3 ve 10 mg/kg’lik dozlarda ligasyondan 15 dakika önce verildi. Deney süresince elektrokardiyografi, kan basıncı ve kalp atımı kayıt edildi. İskemik periyot boyunca aritmi tiplerinin süreleri tespit edildi. Miyokard dokusunda iskemi/reperfüzyon hasarını değerlendirmek için, histopatolojik inceleme yapıldı ve enfarkt alan 2,3,5 -trifenil tetrazolyum klorit boyaması ile tespit edildi. Bulgular: Zileuton 3 mg/kg dozda enfarkt alan ve histopatolojik incelemeler sonucu elde edilen doku hasarı skorunda anlamlı bir azalmaya neden oldu (enfarkt alan [% risk alanı]: zileuton 3 mg/kg %36±7’ye kıyasla kontrol %66±6; p

Cardioprotective effect of zileuton: a 5-lipoxygenase inhibitor against myocardial ischemia/reperfusion injury

Background: This study aims to evaluate the effects of zileuton on myocardial ischemia/reperfusion injury and ischemia-induced ventricular arrhythmias and to investigate the role of 5-lipoxygenase pathway in the pathogenesis of myocardial ischemia/reperfusion injury.Methods: In anesthetized rats, myocardial ischemia was induced by the ligation of the left main coronary artery for 30 min before 120-min reperfusion period. Zileuton was given both at the doses of 3 and 10 mg/kg 15 min before the ligation. During the experiment, electrocardiography, blood pressure, and heart rate were recorded. The duration of arrhythmia types were determined during the ischemic period. To evaluate the ischemia/reperfusion injury in the myocardial tissue, histopathological examination was performed and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining.Results: Zileuton at a dose of 3 mg/kg significantly decreased the infarct size and the tissue injury score obtained using histopathological examinations (infarct size [% of the area at risk]: zileuton 3 mg/kg 36±7% versus control 66±6%, p

PDF

___

31. Sedlis SP. Mechanisms of ventricular arrhythmias in acute ischemia and reperfusion. Cardiovasc Clin 1992;22:3-18.
30. Goulet JL, Snouwaert JN, Latour AM, Coffman TM, Koller BH. Altered inflammatory responses in leukotriene-deficient mice. Proc Natl Acad Sci U S A 1994;91:12852-6.
29. Adamek A, Jung S, Dienesch C, Laser M, Ertl G, Bauersachs J, et al. Role of 5-lipoxygenase in myocardial ischemia-reperfusion injury in mice. Eur J Pharmacol 2007;571:51-4.
28. Maxwell MP, Marston C, Hadley MR, Salmon JA, Garland LG. Selective 5 -lipoxygenase inhibitor BW A4C does not influence progression of tissue injury in a canine model of regional myocardial ischaemia and reperfusion. J Cardiovasc Pharmacol 1991;17:539-45.
27. Wang C, Hu SM, Xie H, Qiao SG, Liu H, Liu CF. Role of mitochondrial ATP-sensitive potassium channel-mediated PKC- in delayed protection against myocardial ischemia/reperfusion injury in isolated hearts of sevoflurane-preconditioned rats. Braz J Med Biol Res 2015;48:528-36.
26. Coetzee WA. Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol Ther 2013;140:167-75.
25. Hahn RA, MacDonald BR, Simpson PJ, Potts BD, Parli CJ. Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size. J Pharmacol Exp Ther 1990;253:58-66.
24. Silva BC, de Miranda AS, Rodrigues FG, Silveira AL, Resende GH, Moraes MF, et al. The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia. Curr Neurovasc Res 2015;12:398-403.
23. Pasnik J and Zeman K. Role of the neutrophil in myocardial ischemia-reperfusion injury. J Organ Dysfunct 2009;5:193-207.
22. Leprán I, Baczkó I, Varró A, Papp JG. ATP-sensitive potassium channel modulators: both pinacidil and glibenclamide produce antiarrhythmic activity during acute myocardial infarction in conscious rats. J Pharmacol Exp Ther 1996;277:1215-20.
21. Curtis MJ, Hancox JC, Farkas A, Wainwright CL, Stables CL, Saint DA, et al. The Lambeth Conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol Ther 2013;139:213-48.
20. Goyal SN, Sharma C, Mahajan UB, Patil CR, Agrawal YO, Kumari S, et al. Protective Effects of Cardamom in Isoproterenol-Induced Myocardial Infarction in Rats. Int J Mol Sci 2015;16:27457-69.
19. Gonca E, Kurt Ç. Cardioprotective effect of Thymoquinone: A constituent of Nigella sativa L., against myocardial ischemia/reperfusion injury and ventricular arrhythmias in anaesthetized rats. Pak J Pharm Sci 2015;28:1267-73.
18. Clark C, Foreman MI, Kane KA, McDonald FM, Parratt JR. Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infarct size. J Pharmacol Methods 1980;3:357-68.
17. Gonca E. The effects of zileuton and montelukast in reperfusion-induced arrhythmias in anesthetized rats. Curr Ther Res Clin Exp 2013;75:27-32.
16. Kwak HJ, Park KM, Choi HE, Lim HJ, Park JH, Park HY. The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKC delta.
15. Silva BC, de Miranda AS, Rodrigues FG, Silveira AL, Resende GH, Moraes MF, et al. The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia. Curr Neurovasc Res 2015;12:398-403.
14. Isikdemir F, Kurcer Z, Dengiz GO, Sipahi EY, Banoglu ZN, Baba F, et al. Effects of montelukast and zileuton on testicular torsion/detorsion injury in rats. Andrologia 2014;46:59-64.
13. Patel NS, Cuzzocrea S, Chatterjee PK, Di Paola R, Sautebin L, Britti D, et al. Reduction of renal ischemia-reperfusion injury in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton. Mol Pharmacol 2004;66:220-7.
12. Kubavat AH, Khippal N, Tak S, Rijhwani P, Bhargava S, Patel T, et al. A randomized, comparative, multicentric clinical trial to assess the efficacy and safety of zileuton extended-release tablets with montelukast sodium tablets in patients suffering from chronic persistent asthma. Am J Ther 2013;20:154-62.
11. Hashimoto H, Miyazawa K, Hagiwara M, Miyasaka K, Nakashima M. Beneficial effects of a new 5-lipoxygenase inhibitor on occlusion- and occlusion -reperfusion-induced myocardial injury. Arzneimittelforschung 1990;40:126-9.
10. Fiedler VB, Mardin M, Perzborn E, Grützmann R. The effects of nafazatrom in an acute occlusion-reperfusion model of canine myocardial injury. Naunyn Schmiedebergs Arch Pharmacol 1985;331:267-74.
9. Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation. Circulation 1992;85:230-6.
8. Sasaki K, Ueno A, Katori M, Kikawada R. Detection of leukotriene B4 in cardiac tissue and its role in infarct extension through leucocyte migration. Cardiovasc Res 1988;22:142-8.
7. Bonaventura A, Montecucco F, Dallegri F. Cellular recruitment in myocardial ischaemia/reperfusion injury. Eur J Clin Invest 2016;46:590- 601.
6. Carbone F, Crowe LA, Roth A, Burger F, Lenglet S, Braunersreuther V, et al. Treatment with anti-RANKL antibody reduces infarct size and attenuates dysfunction impacting on neutrophil-mediated injury. J Mol Cell Cardiol 2016;94:82-94.
5. Singh RK, Gupta S, Dastidar S, Ray A. Cysteinyl leukotrienes and their receptors: molecular and functional characteristics. Pharmacology 2010;85:336-49.
4. Werz O, Steinhilber D. Development of 5-lipoxygenase inhibitors --lessons from cellular enzyme regulation. Biochem Pharmacol 2005;70:327-33.
3. Gerber Y, Weston SA, Enriquez-Sarano M, Berardi C, Chamberlain AM, Manemann SM, et al. Mortality Associated With Heart Failure After Myocardial Infarction: A Contemporary Community Perspective. Circ Heart Fail 2016;9:2460.
2. Arevalo HJ, Vadakkumpadan F, Guallar E, Jebb A, Malamas P, Wu KC, et al. Arrhythmia risk stratification of patients after myocardial infarction using personalized heart models. Nat Commun 2016;7:11437.
1. Huffman MD, Lloyd-Jones DM, Ning H, Labarthe DR, Guzman Castillo M, O'Flaherty M, et al. Quantifying options for reducing coronary heart disease mortality by 2020. Circulation 2013;127:2477-84.