CC BY
12
Usmanova Shakhnoza Erkinovna, Independent researcher of Tashkent Medical Academy,
Republic of Uzbekistan E-mail: [email protected],
EFFECT OF SOME ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS, OMEPRAZOLE, CYTOTEK AND THEIR COMBINATIONS ON PROCESSES OF OXIDATIVE STRESS IN GASTRAL MUCOSA IN INDOMETACIN-INDUCED GASTROPATHY
Abstract: Effect of ACE inhibitors omeprazole and cytotek and their combinations on indices of oxidative stress and NO-formation in gastric mucosa was studied on a model of indometacin-induced gastropathy in rats with experimental rheumatoid arthritis. It was established that aggravation of processes of oxidative stress and reduction in composition of substrates and activity of NO-formation enzymes was one of the causes of injury of stomach with indometacin. Omeprazole, ACE inhibitors and cytotek correct processes disturbed in system of L-arginin-nitrogen oxide and have an antioxidant effect. Captopril and cytotek are most effective in such an effect. In treatment of indometacin-induced gastropathy combined application of omeprazole and ACE inhibitors with cytotek leads to pharmacodynamic reciprocal action as additive synergism.
Keywords: Angiotensin-converting enzyme (ACE) inhibitors (iACE), omeprazole, cytotek, oxidative stress, nitrogen oxide (NO), stomach.
Choice of preparation for treatment of gastropa-thies induced by non-steroid anti-inflammatory drugs (NSAID) in patients with rheumatologic diseases presents significant difficulties first of all because of necessity to conduct anti-ulcerous treatment in continuation of therapy with NSAIDs. NSAIDs cannot be withdrawn even temporarily in many patients admitted to a rheumatologic hospital because of aggravation of main disease, in determination of ulcers or erosions of the upper sections of gastro-intestinal tract because it can result in considerable worsening of a state and aggravation of articular syndrome [1]. Unfortunately, many questions of prophylaxis and effective treatment of NSAID-induced gastropathies are not consummated [2]. Limitedness of arsenal and an insufficient effectiveness, a high frequency of adverse effects of drugs used for treatment and prevention of NSAID-gastropathies exhibit a necessity to work out new effective drugs for treatment of NSAID gastropathies in patients with rheumatic diseases [3].
How it is known, a state of lipid peroxidation (LPO) and NO-formation in gastric mucosa is of no small importance in pathogenesis of NSAID-gastropathies [4].
Recently appeared new data that ACE inhibitors (iACE) have correcting effect on LPO and NO-formation processes in various organs [5]. This circumstance served a base for studying efficacy of some iACE in indometacin-induced gastropathy in animals.
The purpose of the study
Was comparative studying action of some iACE cy-totek, omeprazole and their combinations on LPO and NO-formation processes in gastric mucosa in indometacin-induced gastropathy in animals with experimental rheumatoid arthritis.
Material and methods of research
Experimental studies were carried out on 78 male rats of mixed population with mass 160-200 g that received usual vivarium ration. Animals were distributed into 13 groups with 6 animals in each. The 1st group was intact, the 2nd one - animals with experimental rheumatoid arthritis (ERA.), the 3rd one - animals with ERA. and in-dometacin-induced gastropathy (GERA), the 4th one -GERA+H2 O (without treatment), the 5th one - GERA + enalapril, the 6th one - GERA. + lysinopril, the 7th one -GERA. + captopril, the 8th one - GERA. + omeprazole, the
EFFECT OF SOME ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS, OMEPRAZOL...E
9th one - GERA + cytotek, the 10th one - GERA + omeprazole + enalapril, the 11th one - GERA. + omeprazole + lysinopril, the 12th one - GERA. + omeprazole + captopril, the 13 th one - GERA. + omeprazole + cytotek.
Rheumatoid arthritis was reproduced by a single administration of 0,2 ml Freund's adjuvant into posterior right leg [6]. Indometacin-induced gastropathy was provoked by oral administration of indometacin as water suspension at a dose 2.5 mg/kg during 5 days [7]. The used drugs were administered per os as water suspension during 10 days at the following doses: enalapril 10 mg/kg [8], lysinopril 8 mg/kg [9], captopril 7.5 mg/kg [10], omeprazole 50 mg/kg [11], cytotek 0.2 mg/kg [12]. In combined application drugs were administered in the same doses.
Results obtained were treated with using of Student's test by a standard package of Microsoft Excel. Differences considered valuable in p < 0,05.
Results and discussion
Table 1 presents results of studying effect of iACE, omeprazole and cytotek on indices of LPO in gastric mucosa in indometacin-induced gastropathy in animals with ERA.. How it is seen from the table LPO indices in
Indometacin considerably accelerates processes of oxidative stress. Animals of this group had content of LPO, MDA and chemiluminescent (ChL) 130.4 and 179.0% respectively higher than control values. Activity of catalase was decreasing more than 2.5 times and SOD - more than 2 times.
Inhibitors of ACE omeprazole and cytotek had antioxidant effect on mucosal tissue of stomach. Composition of MDA was decreasing 38.5%, and ChL - 47.7% in animals with enalapril as compared with indices of the group with GERA+H2 O. Activity of catalase was increasing 79.0%, and SOD - 42.8%. Much the same anti-oxidant effect observed to be in rats treated with lysino-pril. But more expressed effect noted to be in treatment with captopril. In this group content of MDA and ChL was decreasing 47.7 and 44.4% respectively, activity of catalase was increasing 103.0%, SOD - 66.7%. Antioxidant effect was also fixed in omeprazole therapy. In rats of this group content of LPO production and activity of AOS enzymes were reliably differed from those in a group without treatment. Antioxidant effect of cytotek was comparable with that in lysinopril group.
ERA were practically not changed.
Table 1. - Indices of oxidative stress in gastric mucosa in indometacin gastropathy in animals with ERA
Group of animals MDA, nmol/min/mg protein ChL, imp/sec Catalase, mcat/min/mg protein SOD, CS/min/mg protein
Control 7.24 ± 0.329 139.8 ± 4.16 101.6 ± 2.95 351. 8 ± 7. 30
ERA 7.51 ± 0.322 135.7 ± 3.96 97.1 ± 2.94 345. 7 ± 7. 38
GERA 16.68 ± 0.550 390.1 ± 5.51 40.1 ± 1.69 165. 6 ± 4. 69
GERA + H2 O 15.52 ± 0.485 375.6 ± 5.98 39.6 ± 1.40 168. 5 ± 4. 08
GERA. + enalapril 9.55 ± 0.345* 196.5 ± 4.40* 70.9 ± 2.99* 240. 7 ± 6. 06*
GERA. + lysinopril 9.14 ± 0.294* 182.4 ± 3.91* 72.8 ± 2.41* 211. 5 ± 4. 66*
GERA + captopril 8.12 ± 0.322* 171.2 ± 4.58* 80.4 ± 2.81* 280. 9 ± 13. 38*
GERA. + omeprazole 12.51 ± 0.454* 218.5 ± 6.92* 60.7 ± 1.98* 207. 3 ± 5. 21*
GERA + cytotek 8.98 ± 0.477* 190.8 ± 4.56* 71.3 ± 3.13* 220. 8 ± 4. 53*
GERA. + omeprazole + enalapril 7.85 ± 0.282* 176.1 ± 4.40* 80.6 ± 3.03* 270. 6 ± 4. 89*
GERA. + omeprazole + lysinopril 7.11 ± 0.241* 170.4 ± 3.56* 83.5 ± 3.17* 285. 4 ± 8. 05*
GERA + omeprazole + captopril 5.12 ± 0.193* 150.8 ± 3.20* 89.5 ± 3.19* 321. 3 ± 7. 29*
GERA. + omeprazole + cytotek 6.08 ± 0.201* 147.3 ± 4.40* 93.7 ± 2.54* 315. 1 ± 6. 96*
Note:* р < 0,05 as compared with indices of animals without treatment
Antioxidant effect of combination of omeprazole and other drugs was potentiated. In group of omeprazole + enalapril composition of MDA and ChL was decreas-
ing compared with a group without therapy 49.5% and 53.2% respectively. It was fixed also a more expressed increase in activity of catalase 103.5% and SOD 60.6%. In
group of omeprazole + lysinopril composition of MDA, ChL and activity of catalase were practically not differed from that in group of omeprazole + enalapril. Activity of SOD was only reliably high. Decrease in content of LPO products and increase in activity of AOS enzymes was significant in animals treated with omeprazole + cap-topril. The studying indices were reliably differed from control ones. Content of MDA and ChL was decreasing 67.1% and 59.9%, activity of catalase was increasing 126.0%, SOD - 90.7%. In group of omeprazole + cytotek composition of MDA and ChL was decreasing 60.9% and 60.8% respectively, and activity of catalase and SOD was increasing 136.6% and 87.0%.
Conclusion
1. One of the causes of injury of stomach with indo-metacin is intensification of processes of oxidative stress and reduction of content of substrate and activity of NO-formation enzymes.
2. Omeprazole, inhibitors of angiotensin-converting enzymes (ACE) and cytotek correct processes disordered in a system of L-arginin - nitrogen oxide and have an antioxidant effect. Captopril and cytotek are the most effective in this effect.
3. Combined application of omeprazole and ACE inhibitors and cytotek leads to pharmacodynamic reciprocal action as additive synergism in treatment of indo-metacin-induced gastropathy.
References:
1.
2.
3.
4.
5.
6.
7.
Насонова В. А. Гастропатии, связанные с приемом нестероидных противовоспалительных препаратов // Рос.журн.гастроэнтерол., гепатол., копроктол. - 1994. -№ 1.- С. 7-10.
Гастропатия, обусловленная НПВП: от понимания механизмов раз-вития к разработке стратегии лечения и профилактики / В. А. Ахмедов, В. А. Винжегина, А. Н. Судакова, Е. И. Розенблит // Тер.арх. - 2007. -№ 2. - С. 81-85.
ШептулинА. А. Современные возможности лечения и профилактики НПВП-индуцированной гастропатии // Рос.журн. гастроэнтерол., гепатол., копроктол. - 2006. - № 1. - С. 15-19.
Покровский В. И., Виноградов Н. А. Оксид азота, его физиологические и патофизиологические свойства // Тер.арх. - 2005. - № 1. - С. 82-87.
Подзолков В. И., Осадчий К. К. Ингибиторы АПФ в лечении артериальной гипертензии: фокус на лизино-прил // Рациональная фармакотерапия в кардиол. - 2009. - № 1. - С. 57-62.
Экспериментальный ревматоидный артрит / О. В. Синяченко, Э. Ф. Баринов, С. В. Зяблицев [и др.] // Ревматология. -1991. - № 3. - С. 36-40.
Cyclooxigenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity / J. L. Wallace, A. Bak, W. Mckhight [et al.] // Gastroenterology. - 1998. - Vol. 115. - P. 101-109.
8. Тимошин С. С. Участие нейропептидов в поддержании тканевого гомеостаза слизистой оболочки желудочно-кишечного тракта // Материалы XVI сессии Академической школы-семинара им. А. М. Уголева и современные проблемы физиологии и патологии пищеварения // Рос.журн. гастроэнтерол., гепатол., колопроктол. - 2001. - № 4. - С. 38-43.
9. Оценка гипотензивного эффекта и побочного действия генерического препарата лизиноприл / М. В. Ковалева, В. Ю. Афонин, В. В. Шилов [и др.] // Актуальные проблемы токсикологии и радиобиологии: Материалы Рос.науч.конф. с междунар. участием. - СПб, 2011. - 17 c.
10. Captopril increased mitochondrial coenzyme Q10 level, improved respiratory chain function and energy production in the left ventricle in rabbits with smoke mitochondrial cardiomyopathy / A. Gvozdjakova, F. Simko, J. Kucharska [et al.] // J. Biofactors. - 1999. - Vol. 10. - No. 1. - P. 61-65.
11. Даминов Ш. Н., Иноятова Ф. Х. Сравнительная оценка действия кваматела и омеза на систему глутатиона различных отделов пищеварительной системы при экспериментальной язве двенадцатиперстной киш-ки//Экспер. и клин.фармакол. - 1998. - № 4. - С. 26-28.
12. Effects of Misoprostol on Methotrexate-Induced Hepatic and Renal Damages / H. Asci, M. K. Ozer, M. Calapoglu [et al.] // J. Biol. Life Sci. - 2011. - Vol. 2. - No. 1. - Р. 32-37.
