The role of losartan and enalapril in the protection against stress-induced gastric mucosal ulceration in rats

Sanaa A. Ahmed, Mahmoud H. Abdel-Rahim, Hytham M. Abdel-latif


Background: Angiotensin II (ANG II) is a stress hormone and its level dramatically increases in the stomach during stress. In addition, it generates reactive oxygen species (ROS) with cellular damage and inflammation. So the aim of this study is to evaluate the mechanism of losartan and enalapril in the prevention of stress-induced gastric ulcer through their action on mucosal prostaglandin (PGs) and antioxidant enzymes and compare between them.

Methods: Thirty- six adult male wistar albino rats weighing 180-200 g were divided into 6 groups; n= 6. Groups 1, 2, and 3 were received saline (normal control), losartan (3 mg/kg/day) and enalapril (10 mg/kg/day) i.p respectively for 4 weeks. Groups 4, 5, and 6 were pretreated with saline (ulcer control), losartan (3 mg/kg/day) and enalapril (10 mg/kg/day) i.p respectively for 4 weeks duration. On 29th day, group 4, 5 and 6 were submitted to gastric ulcer by water immersion method, then animals of all groups were sacrificed, stomachs were excised for gross and microscopic examination and determination of the mucosal levels of prostaglandin E2 (PGE2), superoxide dismutase (SOD), nitric oxide (NO) and catalase (CAT).

Results: Stress produced gastric ulcer and a significant decrease in all measured gastric parameters compared to normal control group. Pre-treatment of rats with losartan or enalapril decreased the stress-induced alterations in mucosal parameters, but only losartan caused a significant increase in CAT activity in addition.

Conclusions: Antagonize the action of ANG II by losartan and enalapril have preventive advantages in stress-induced gastric ulcer and losartan has better influence as it has an additional effect on CAT activity.


Losartan, Enalapril, Gastric ulcer, PGE2, SOD, Nitric oxide, Catalase

Full Text:



Wang Y, Richter J, Dempsey D. Trends and outcomes of hospitalizations for peptic ulcer disease in the United States, 1993 to 2006. Ann Surg. 2010;251:51-8.

Jain K, Shah A, Bariwal J. Recent advances in proton pump inhibitors and management of acid-peptic disorders. Bioorg Med Chem. 2007;15:1181-205.

Parente L, Parretti M. Advances in the pathophysiology of constitutive and inducible cyclooxygenases. Biochem Pharmacol. 2003;65:153-9.

Bregonzio C, Armando I, Ando H. Anti-inflammatory effects of angiotensin II AT1 receptor antagonism prevents stress-induced gastric injury. Am J Physiol Gastrointest Liver Physiol. 2003;285(2):414-23.

Dongcheng M, Xueguang Z, Wei X. The pathogenic role of endogenous angiotensin II in stress ulcer in obstructive jaundice rats. Chin Med J. 1998;111:309-12.

Carl-McGrath S, Grantzdorffer I, Lendeckel U. Angiotensin II-generating enzymes, angiotensin-converting enzyme (ACE) and mast cell chymase (CMA1), in gastric inflammation may be regulated by H. pylori and associated cytokines. Pathology. 2009;41:419-27.

Heinemann A, Sattler V, Jocic M. Effect of angiotensin II and telmisartan, an angiotensin I receptor antagonist, on gastric mucosal blood flow. Aliment Pharmacol Ther. 1999;13:347-55.

Touyz R. Reactive oxygen species and angiotensin II signaling in vascular cells: implications in cardiovascular disease. Brazilian J Med Biological Research. 2004;37(8):1263-73.

Tandon R, Khanna H, Dorababu M. Oxidative stress and antioxidants status in peptic ulcer and gastric carcinoma. Indian J Physiol Pharmacol. 2004;48:115-8.

Shiotani A, Sakakibara T, Yamanaka Y. Upper gastrointestinal ulcer in Japanese patients taking low-dose aspirin. J Gastroenterol. 2009;4:126-31.

Ueyama T, Saika M, Koreeda C, Senba E. Water immersion restraint stress induces expression of immediate early genes in gastrointestinal tract of rats. Am J Physiol. 1998;275(2pt1):287-95.

Nakagiri A, Sunamoto M, Murakami M. Angiotensin AT1 receptor blockers suppress ischemia/reperfusion induced gastric injury in rats. Inflammopharmacol. 2007;15(4):171-4.

Baluchnejadmojarad T, Roghani M, Imani A. Protective effect of enalapril on vascular reactivity of the rat aorta. Vasc Pharmacol. 2004;40:301-7.

Fernández N, Alonso S, Valera I, Vigo A. Mannose-containing molecular patterns are strong inducers of cyclooxygenase-2 expression and prostaglandin E2 production in human macrophages. J Immunol. 2005;174:8154-62.

Nishikimi M, Roa A, Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun. 1972;64(2):849-54.

Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121-6.

Montgomery H, Dymock J. The determination of nitrite in water. Analyst. 1961;86:414-6.

Cai H, Griendling K, Harrison D. The vascular NAD (P) H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci. 2003;24(9):471-8.

Ajaikumar K, Asheef M, Babu B. The inhibition of gastric mucosal injury by Punicagranatum L. (pomegranate) methanolic extract. J Ethnopharmacol. 2005;96(1):171-6.

Tanaka A, Hatazawa R, Takahira Y. Preconditioning stress prevents cold restraint stress-induced gastric lesions in rats: roles of COX-1, COX-2, and PLA2. Dig Dis Sci. 2007;52(2):478-87.

Suleyman H, Albayrak A, Bilic M, Cadirci E. Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers. Inflammation. 2010;33(4):224-34.

Bhatia V, Tandon R. Stress and the gastrointestinal tract. J Gastroenterol Hepatol. 2005;20(3):332-9.

Andrade T, Graeff F. Effect of electrolytic and neurotoxic lesions of the median raphe nucleus on anxiety and stress. Pharmacol Biochem Behav. 2001;70(1):1-14.

Guo G, Jia K, Shi Y, Liu X, Liu K, Qi W. Psychological stress enhances the colonization of the stomach by helicobacter pylori in the BALB/c mouse. Stress. 2009;12(6):478-85.

Morsy M, Heeba G, Abdelwahab S. Protective effects of nebivolol against cold restraint stress-induced gastric ulcer in rats: Role of NO, HO-1, and COX-1, 2. Nitric Oxide. 2012;27(2):117-22.

Seo P, Kim N, Kim J. Comparison of indomethacin, diclofenac and aspirin-induced gastric damage according to age in rats. Gut Liver. 2012;6(2):210-7.

Fouad A, Al-Sultan A, Yacoubi M. Ameliorative effects of telmisartan in diabetic rats with indomethacin-induced gastric ulceration. Eur J Pharmacol. 2010;637(1):162-70.

Brzozowski T, Konturek P, Konturek S. Role of prostaglandins in gastroprotection and gastric adaptation. J Physiol Pharmacol. 2005;5:33-55.

Swartz S, Williams G, Hollenberg N. Captopril-induced Changes in Prostaglandin Production relationship to vascular response in normal man. J Clin Invest. 1980;65(6):1257-64.

Molina‐Molina M, Serrano‐Mollar A, Bulbena O. Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis. Thorax. 2006;61(7):604-10.

Fridovich I. Biological effects of superoxide radical. Arch Biochem Biophy. 1986;247:1-11.

Chandran G, Sirajudeen K, Yusoff N, Swamy M. Effect of the antihypertensive drug enalapril on oxidative stress markers and antioxidant enzymes in the kidney of spontaneously hypertensive rats. Oxid Med Cell Longev. 2014;2014:608512.

Khaper N, Singal P. Modulation of oxidative stress by a selective inhibition of angiotensin II type 1 receptors in MI rats. J Am Coll Cardiol. 2001;37(5):1461-6.

Ivanov M, Mihailović-Stanojević N, Milanović J. Losartan improved antioxidant defense, renal function and structure of postischemic hypertensive kidney PLoS one. 2014;9(5):1-7.

De Cavanagh E, Inserra F, Ferder L. Superoxide dismutase and glutathione peroxidase activities are increased by enalapril and captopril in mouse liver. FEBS Lett. 1995;361(1):22-4.

Calatayud S, Sanz M, Canet A. Mechanisms of gastroprotection by transdermal nitroglycerin in the rat. Br J Pharmacol. 1999;127:1111-8.

Mollace V, Muscoli C, Masini E. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol Rev. 2005;57(2):217-52.

Boveris A, D'Amico G, Lores-Arnaiz S. Enalapril increases mitochondrial nitric oxide synthase activity in heart and liver. Antioxid Redox Signal. 2003;5(6):691-7.

Morsy M, Ashour O, Amin E. Gastroprotective effects of telmisartan on experimentally induced gastric ulcers in rats. Pharmazie. 2009;64(9):590-4.

Donmez G, Derici U, Erbas D. The effects of losartan and enalapril therapies on the levels of nitric oxide, malondialdehyde, and glutathione in patients with essential hypertension. J Physiol. 2002;52(5):435-40.

Yu X, Zhang D, Jia L, Qi J. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress. Toxicol Appl Pharmacol. 2015;284(3):315-22.

Koh E, Yoon S, Lee S. Losartan protects the liver against ischemia/reperfusion injury through PPAR-γ activation and receptor for advanced glycation end-products down-regulation. Br J Pharmacol. 2013;169(6):1404-16.

Nakamura T, Keep R, Hua Y. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039(1):30-6.

Zhou Y, Zhao L, Zhang Z, Lu X. Protective Effect of enalapril against methionine-enriched diet-induced hypertension: role of endoplasmic reticulum and oxidative stress. Biomed Res Int. 2015;724876.