FAİZE ELİF BAHADIR, Muhammet BULUT, Beyza KABAYUKA, Ece ŞENKALSÖYLEM, Abdullah YALVAÇ, MERAL YÜKSEL, FERİHA ERCAN, YAŞAR İNCİ ALİCAN

Sıçanda stres ile uyarılan mide ülserinde simvastatin'in etkisi

Amaç: Bu çalışmada sıçanlarda stres ile uyarılan mide ülserinde simvastatin (SİM)'in olası koruyucu etkisini değerlendirmek amaçlanmıştır. Gereç ve Yöntem: Sprague-Dawley sıçanlarda (250-300 gr) soğuk-kısıtlama stresi uygulaması ile mide ülseri oluşturuldu. Stres öncesi 21 gün süreyle SİM (10 mg/kg/gün; oral yolla) veya fizyolojik tuzlu su (1 ml; oral yolla) uygulandı. Bir grup sıçan 21. günde SİM öncesi selektif olmayan nitrik oksit sentaz (NOS) inhibitörü L-NAME (50 mg/kg; intraperitoneal) veya selektif olmayan siklooksijenaz (COX) inhibitörü indometazin (İndo; 5 mg/kg; subkutan) verildi. Mideler makroskopik ve mikroskopik olarak incelendi ve biyokimyasal analizler için saklandı.Bulgular: Stres grubunda lezyonların şiddeti SİM ile azaldı ancak L-NAME veya İndo ile anlamlı bir değişiklik göstermedi. Stres mide miyeloperoksidaz aktivitesini kontrol düzeyine kıyasla artırdı (p

The effect of simvastatin pretreatment on stress-induced gastric ulcer in rats

Objectives: This study aimed to elucidate the possible protective effect of simvastatin (SIM) pretreatment on stress-induced gastric ulcer in rats. Materials and Methods: Gastric ulcer was produced in Sprague-Dawley rats (250-300 g) by cold-restraint stress. SIM (10 mg/kg/day; per oral) or saline was administered for 21 days prior to stress. On day-21, a group of animals was treated with the non-selective nitric oxide synthase (NOS) inhibitor L-NAME (50 mg/kg; intraperitoneally) or the non-selective cyclooxygenase (COX) inhibitor indomethacin (Indo; 5 mg/kg; subcutaneously) prior to SIM. The stomachs were examined macroscopically and microscopically and stored for biochemical analyses.Results: The severity of the lesions of the stress group was decreased by SIM, but this was not altered significantly by L-NAME or Indo. Stress increased gastric myeloperoxidase activity compared to control level (p<0.01); however, SIM did not cause a significant change on this parameter. Stress increased gastric chemiluminescence levels (p<0.001) which were reversed by SIM (p<0.001) and this effect continued in L-NAME- or Indotreated animals. Conclusion: SIM pretreatment of rats with cold-restraint stress provided partial protection against gastric lesion formation via suppression of oxidants derived from sources other than neutrophils without the involvement of NOS and COX systems.

PDF

___

1. Corsini A, Maggi FM, Catapano AL. Pharmacology of competitive inhibitors of HMG-CoA reductase. Pharmacol Res 1995;31:9-27. doi:10.1016/1043-6618(95)80042-5.
2. Simes J, Furberg CD, Braunwald E, et al. Effects of pravastatin on mortality on patients with and without coronary heart disease across a broad range of cholesterol levels. Eur Heart 2002;23:207-15.
3. The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.
4. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Bere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22. doi:10.1001/jama.279.20.1615.
5. Liao JK. Effect of statins on 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005;96:24F-33F. doi:10.1016/j.amjcard.2005.06.009.
6. Werner N, Nickeniq G, Laufs U. Pleiotropic effects of HMGCoA reductase inhibitors. Basic Res Cardiol 2002;97:105-16.
7. Trochu JN, Mital S, Zhang Xp, et al. Preservation of NO production by statins in treatment of heart failure. Cardiovasc Res 2003;60:250-8. doi: http://dx.doi.org/10.1016/j. cardiores.2003.08.003.
8. Jiang JL, Jiang DJ, Tang YH, Li NS, Deng HW, Li YJ. Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor. Acta Pharmacol Sin 2004;25:893-901.
9. Dobrucki LE, Kalinowski L, Dobrucki IT, Malinski T. Statinstimulated nitric oxide release from endothelium. Med Sci Monit 2001;7:622-7.
10. Schror K, Lobel P, Steinhagen-Thiessen E. Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia. Eicanosoids 1989;2:39-45.
11. Scalia R, Gooszen ME, Jones SP, et al. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apoliprotein E-deficient mice. Circulation 2001;103:2598-603. doi: 10.1161/01.CIR.103.21.2598.
12. Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocytes- endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol 1999;19:2894-900. doi: 10.1161/01.ATV.19.12.2894.
13. Ungureanu D, Filip C, Artenie A, Artenie R. Evaluation of simvastatin antioxidant effects. Rev Med Chir Soc Med Nat 2003;107:66-71.
14. Naidu BV, Woolley SM, Farivar AS, Thomas R, Fraga C, Mulligan MS. Simvastatin ameliorates injury in experimental model of lung ischemia-reperfusion. J Thorac Cardiovasc Surg 2003;126:482-9. doi:10.1016/S0022-5223(03)00699-8.
15. Inman SR, Davis NA, Olson KM, Lukaszek VA. Simvastatin attenuates renal ischemia/reperfusion injury in rats administered cyclosporine A. Am J Med Sci 2003;326:117- 21.
16. Rendig SV, Symons JD, Amterdam EA. Effects of statins on myocardial and coronary artery response to ischemiareperfusion. Can J Physiol Pharmacol 2003;81:1064-71. doi: 10.1139/y03-105.
17. Shabanzadeh AP, Shuaib A, Wang CX. Simvastatin reduced ischemic brain injury and perfusion deficits in an embolic model of stroke. Brain Res 2005;1042:1-5. doi:10.1016/j. brainres.2005.01.105.
18. Tariq M, Khan HA, Elfaki I, et al. Gastric antisecretory and antiulcer effects of simvastatin in rats. J Gastroenterol Hepatol 2007;22:2316-23. doi: 10.1111/j.1440-1746.2007.05021.x.
19. Heeba GH, Hassan MKA, Amin RS. Gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats: role of nitric oxide and prostaglandins. Eur J Pharmacol 2009;607:188-93. doi: 10.1016/j.ejphar.2009.02.008.
20. Yeomans N. The ulcer sleuths: the search for the cause of peptic ulcers. J Gastroenterol Hepatol 2011;26:35-41. doi: 10.1111/j.1440-1746.2010.06537.x.
21. Senay EC, Levine RJ. Synergism between cold and restraint for rapid production of stress ulcer in rats. Proc Soc Exp Biol Med 1967;124:1221-3.
22. Jahovic N, Erkanli G, Işeri S, Arbak S, Alican I. Gastric protection by alpha-melanocyte-stimulating hormone against ethanol in rats: involvement of somatostatin. Life Sci 2007;80(11):1040-5. doi:10.1016/j.lfs.2006.11.036.
23. Aykac G, Uysal M, Yalcin AS, Kocak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione peroxidase and glutathione transferase in rat. Toxicology 1985:46:71-6.
24. Casini A, Ferrali M, Pompella AS, Maellaro E, Comporti M. Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene intoxicated mice. Am J Pathol 1986: 123:520-31.
25. Bradley PP, Preibat D, Christerser RD, Rothstein G. Measurement of cutaneous inflammation, estimation of neutrophil content with an enzyme marker. J Invest Dermatol 1982:78:206-9.
26. Haklar G, Ulukaya-Durakbasa C, Yuksel M, Dagli T, Yalcin AS. Oxygen radicals and nitric oxide in rat mesenteric ischemia-reperfusion: modulation by L-arginine and N-nitroL-arginine methyl ester. Clin Exp Pharmacol Physiol 1998;25:908-12. doi: 10.1111/j.1440-1681.1998.tb02342.x.
27. Kwiecien S, Brzozowski T, Konturek SJ. Effects of reactive oxygen species action on gastric mucosa in various models of mucosal injury. J Physiol Pharmacol 2002;53:39-50.
28. Brzozowski T, Konturek PC, Pajdo R, et al. Physiological mediators in nonsteroidal anti-inflammatory drugs (NSAIDs)- induced impairment of gastric mucosal defense and adaptation. Focus on nitric oxide and lipoxins. J Physiol Pharmacol 2008;59:89-102.
29. Kwiecien S, Brzozowski T, Konturek PC, et al. Gastroprotection by pentoxyfilline against stress-induced gastric damage. Role of lipid peroxidation, antioxidizing enzymes and proinflammatory cytokines. J Physiol Pharmacol 2004;55:337-55.
30. Kwiecien S, Brzozowski T, Konturek PC, et al. The role of reactive oxygen species and capsaicin-sensitive sensory nerves in the pathomechanism of gastric ulcers induced by stress. J Physiol Pharmacol 2003;54:423-37.
31. Konturek SJ, Konturek PC. Role of nitric oxide in digestive system. Digestion 1995;56:1-13.
32. Sparrow CP, Burton CA, Hernandez M, et al. Simvastation has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler Thromb Vasc Biol 2001;21:115-21. doi: 10.1161/01. ATV.21.1.115.
33. Jahovic N, Gedik N, Ercan F, et al. Effects of statins on experimental colitis in normocholesterolemic rats. Scand J Gastoenterol 2006;41:954-62. doi: 10.1080/00365520600554444.
34. Bjarnason I, Scarpignato C, Takeuchi K, Rainsford KD. Determinants of the short-term gastric damage caused by NSAIDs in man. Aliment Pharmacol Ther 2007;26:95-106. doi: 10.1111/j.1365-2036.2007.03348.x.
35. Lopez-Belmonte J,Whittle BJ,Moncada S. The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol 1993;108(1):73-8. doi: 10.1111/j.1476-5381.1993.tb13442.x.
36. Matsui H, Shimokawa O, Kaneko T, Nagano Y, Rai K, Hyodo I. The pathophysiology of non-steroidal antiinflammatory drug (NSAID)-induced mucosal injuries in stomach and small intestine. J Clin Biochem Nutr 2011;48:107-11. doi: http://doi. org/10.3164/jcbn.10-79.
37. Konturek SJ, Piastucki I, Brzozowski T, et al. Role of prostaglandins in the formation of aspirin-induced gastric ulcers. Gastroenterology 1981;80:4-9