Deniz ŞAHİN, Fatma Ceyla ERALDEMİR, Şadan YAVUZ, Ali Ahmet ARIKAN, Hale Maral, Ömer Faruk GÜLAŞTI, Tolga KURT, Ersan ÖZBUDA

Sıçan alt ekstremite iskemi-reperfüzyon modelinde rivaroksaban ve klopidogrelin değerlendirilmesi: Deneysel bir çalışma

Amaç: Bu çalışmada, uzun bir reperfüzyon süresinden sonra iskemireperfüzyon hasarına karşı klopidogrel ve rivaroksaban karşılaştırıldı ve çeşitli dokular üzerindeki etkileri araştırıldı. Çalışma planı: Toplamda 40 Wistar sıçan çalışmaya dahil edildi ve rastgele dört gruba ayrıldı (grup başına n=10). Gruplar şu şekilde belirlendi: kontrol (Grup 1), sham (Grup 2), klopidogrel ön tedavisi (Grup 3) ve rivaroksaban ön tedavisi (Grup 4). Grup 2, 3 ve 4'te sıçanların arka bacaklarında iskemi (6 saat) ve reperfüzyon (8 saat) indüklendi. Oksidan (malondialdehit) ve antioksidanları (glutatyon, süperoksit dismutaz ve nitrik oksit) çalışmak için, deneklerin iskemik kas, kalp, böbrek, karaciğer ve plazma dokuları incelendi. Bulgular: Malondialdehit sham grubunda tüm dokularda kontrollere kıyasla anlamlı düzeyde yüksekti. Klopidogrel ve rivaroksaban ön tedavisi sham grubun kalp, iskemik kas, karaciğer ve kan dokularında malondialdehit düzeylerini anlamlı düzeyde düşürdü. Böbrek malondialdehit düzeyleri, yalnızca rivaroksaban ile azaldı. Grup 4’te, Grup 3'e kıyasla, iskemik kasta malondialdehit anlamlı düzeyde düşük bulundu (p

An evaluation of rivaroxaban and clopidogrel in a rat lower extremity ischemia-reperfusion model: An experimental study

Background: This study aims to compare clopidogrel and rivaroxabanagainst ischemia-reperfusion injury after a long reperfusion time and toinvestigate its effects on various tissues.Methods: A total of 40 Wistar rats were included in the study and wererandomly divided into four groups (n=10 per group). Groups were definedas follows: control (Group 1), sham (Group 2), clopidogrel pre-treatment(Group 3), and rivaroxaban pre-treatment (Group 4). Ischemia (6 h) andreperfusion (8 h) were induced at the lower hind limb in Groups 2, 3, and 4.The ischemic muscle, heart, kidney, liver, and plasma tissues of the subjectswere obtained to test for the oxidant (malondialdehyde) and antioxidants(glutathione, superoxide dismutase, and nitric oxide).Results: Malondialdehyde levels were significantly higher in thesham group, compared to the controls in all tissues. Clopidogrel andrivaroxaban pre-treatment significantly decreased malondialdehydelevels, compared to the heart, ischemic muscle, liver, and blood tissuesof the sham group. Kidney malondialdehyde levels were reduced onlyby rivaroxaban. Group 4 had significantly decreased malondialdehydelevels, compared to Group 3 in ischemic muscle (p

PDF

___

1. Parks DA, Granger DN. Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 1986;250:749-53.
2. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med 2017;377:1319-30.
3. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219-29.
4. Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). mEur Heart J 2018;39:763-816.
5. Demirtas S, Karahan O, Yazıcı S, Guclu O, Calıskan A, Tezcan O, et al. Investigation of possible prophylactic, renoprotective, and cardioprotective effects of thromboprophylactic drugs against ischemia-reperfusion injury. Kaohsiung J Med Sci. 2015;31:115-22.
6. Yassin MM, Harkin DW, Barros D’Sa AA, Halliday MI, Rowlands BJ. Lower limb ischemia-reperfusion injury triggers a systemic inflammatory response and multiple organ dysfunction. World J Surg 2002;26:115-21.
7. Eltzschig HK, Collard CD. Vascular ischaemia and reperfusion injury. Br Med Bull 2004;70:71-86.
8. Kanko M, Maral H, Akbas MH, Ozden M, Bulbul S, Omay O, et al. Protective effects of clopidogrel on oxidant damage in a rat model of acute ischemia. Tohoku J Exp Med 2005;205:133-9.
9. Kanko M, Ozden M, Maral H, Acil C. Effect of clopidogrel on nitric oxide levels in an ischemia reperfusion model. J Cardiovasc Pharmacol 2006;48:797-801.
10. Caliskan A, Yavuz C, Karahan O, Yazici S, Guclu O, Demirtas S, et al. Factor-Xa inhibitors protect against systemic oxidant damage induced by peripheral-ischemia reperfusion. J Thromb Thrombolysis 2014;37:464-8.
11. Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978;52:302-10.
12. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70-7.
13. Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 1990;36:1440-3.
14. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-75.
15. Carden DL, Granger DN. Pathophysiology of ischaemiareperfusion injury. J Pathol 2000;190:255-66.
16. Hosseini F, Naseri MK, Badavi M, Ghaffari MA, Shahbazian H, Rashidi I. Effect of beta carotene on lipid peroxidation and antioxidant status following renal ischemia/reperfusion injury in rat. Scand J Clin Lab Invest 2010;70:259-63.
17. Grip O, Wanhainen A, Michaëlsson K, Lindhagen L, Björck M. Open or endovascular revascularization in the treatment of acute lower limb ischaemia. Br J Surg 2018;105:1598-1606.
18. Kunt AT, İsbir S, Civelek A, Akgun S, Ergen A, Yapicier O, et al. Prevention of lung injury by iloprost following hind limb ischemia and reperfuison model in rats. Turk J Clin Lab 2018;9:76-80.
19. Yeginsu A, Ergin M, Özyurt H, Elmaz Ç, Akbaş A, Çağlar Göktaş G, et al. The effects of methylprednisolone on the lung injury resulted from extremity ischemia reperfusion. Turk Gogus Kalp Dama 2010;18:45-51.
20. O’Connell JB, Quiñones-Baldrich WJ. Proper evaluation and management of acute embolic versus thrombotic limb ischemia. Semin Vasc Surg 2009;22:10-6.
21. Wang XT, Tian Y, Xu WX, Cui LH, Xiang SY, Lü SC. Protective effects of modeled superoxide dismutase coordination compound (MSODa) against ischemia/ reperfusion injury in rat skeletal muscle. Cell Physiol Biochem 2015;37:465-76.
22. Glantzounis GK, Salacinski HJ, Yang W, Davidson BR, Seifalian AM. The contemporary role of antioxidant therapy in attenuating liver ischemia-reperfusion injury: a review. Liver Transpl 2005;11:1031-47.
23. Peralta C, Hotter G, Closa D, Gelpí E, Bulbena O, Roselló-Catafau J. Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine. Hepatology 1997;25:934-7.
24. Jones SP, Girod WG, Palazzo AJ, Granger DN, Grisham MB, Jourd’Heuil D, et al. Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase. Am J Physiol 1999;276:H1567-73.
25. Rubbo H, Darley-Usmar V, Freeman BA. Nitric oxide regulation of tissue free radical injury. Chem Res Toxicol 1996;9:809-20.
26. Yavuz C, Yazici S, Karahan O, Demirtas S, Caliskan A, Guclu O, et al. Serum nitric oxide level could be a predictive biomarker for detection of critical ischaemia duration. Biomarkers 2013;18:116-20.
27. Samama MM. The mechanism of action of rivaroxaban- -an oral, direct Factor Xa inhibitor--compared with other anticoagulants. Thromb Res 2011;127:497-504.
28. Goto M, Miura S, Suematsu Y, Idemoto Y, Takata K, Imaizumi S, et al. Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice. Int J Cardiol 2016;220:602-7.