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Usmanova Shakhnoza Erkinovna, Independent researcher of Tashkent Medical Academy,
Republic of Uzbekistan Yakubov Abdujalol Vahabovich, Head of the department of Clinical Pharmacology of Tashkent Medical Academy, Republic of Uzbekistan
Hamraev Abror Asrarovich, Professor of the department of Internal Medicine № 2 of Tashkent Medical Academy Republic of Uzbekistan
E-mail: evovision@bk.ru,
STATE OF GASTRIC MUCOUS BARRIER IN INDOMETACIN-INDUCED GASTROPATHY. EFFECTS OF USING INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME, OMEPRAZOLE AND MISOPROSTOL
Abstract: on experimental model of indometacin-induced gastropathy in rats with rheumatoid arthritis was studied effectiveness of peroral administration of enalapril at a dose 10 mg/kg, lysino-pril - 8 mg/kg, captopril - 7,5 mg/kg, omeprazole - 50 mg/kg, misoprostol - 0,2 mg/kg during 10 days on content of fractions of insoluble glycoproteins in gastric mucosa.
It was established that damage of gastric mucosa in indometacin-induced gastropathy was characterized by reduction in composition of carbohydrate and protein fractions of glycoproteins. I-ACE -enalapril, lysinopril and captopril increase composition of glycoproteins in gastric mucosa. In this effect captopril excels enalapril and lysinopril. In its cytoprotective effect captopril equates to misoprostol.
Keywords: gastropathy, rheumatoid arthritis, I-ACE, omeprazole, misoprostol.
In the last decade a problem of NSAID-gastropathy O. M. Mikheyeva et al. [2] serve this confirmation that
takes an important place in treatment of rheumatologic established ulcer-healing effect of enalapril on hyperten-patients. Search for new mechanisms of development of sion patients with concomitant ulcer disease. As early as
USAID-gastropathy and elaboration of new therapeu- 2004 S. A. Alexeyenko et al. [3] noted improvement of
tic drugs for treatment and prevention subject to data clinical course of chronic gastritis in patients with arterial
received are carried out [1]. At present for prevention hypertension in treatment with enalapril and lysinopril. and treatment of USAID -gastropathies are substantially Nafeeza Mohd Ismail et al. [4] on a model of aspirin-
used anti-secretory means and synthetic analogues of induced gastropathy in rats studied an effect of captopril prostaglandins. But how shows practice preparations of and ranitidine on content of prostaglandin E2, malonic
these groups are scanty effective for prevention and treat- dialdehyde and on activity of glutathione reductase. It
ment of USAID-gastropathies and are not suitable for was established that captopril unlike ranitidine increases
prolonged use through their adverse effects. activity of glutathione reductase, content of prostaglan-
To solve a problem of effective and safe prevention din E2 and reliably decreases content of malonic dialde-
and treatment of USAID-gastropathies we consider hyde (MDA).
reasonable to use inhibitors of angiotensin-converting Aim of study. The given study was aimed at compar-
enzyme (I-ACE). It is known that I-ACE has stimulat- ative research of effectiveness of omeprazole, enalapril,
ing effect on synthesis ofprostaglandins (PG-E2) in kid- lysinopril, captopril and misoprostol on a state of gastric
neys, vessels, and brain. It is assumed that they provoke mucous barrier on a model of NSAID-gastropathy in rats
an analogous effect in gastrointestinal tract. Studies of with rheumatoid arthritis.
STATE OF GASTRIC MUCOUS BARRIER IN INDOMETACIN-INDUCED GASTROPATHY EFFECTS.
Materials and methods:
Experimental studies were carried out on 54 male rats of mixed population weighting 160-200g that were on habitual ration of vivarium. Animals were divided into the following groups:
1st group - intact; 2nd group - animas with experimental rheumatoid arthritis (ERA); 3rd group - animals with ERA and indometacin gastropathy (GERA); 4th group - GERA + distilled water during 10 days (group without treatment); 5th group - GERA + enalapril; 6th group - GERA + lysinopril; 7th group - GERA + Captopril; 8th group - GERA + omeprazole; 9th group - GERA + misoprostol.
Experimental model of rheumatoid arthritis was induced by single administration of 0,2 ml Freund's adjuvant into hind right leg [8; 9]. Indometacin-induced gastropathy was caused by administration of indometacin water suspension at a dose 2,5 mg/kg per os during 5 days [5].
Preparations studying were administered as water suspension in the following doses: enalapril at a dose 10 mg/kg [6], lysinopril - 8 mg/kg [7], captopril -7.5 mg/kg [8], omeprazole - 50 mg/kg, misoprostol -0.2 mg/kg [9]. Selecting doses of the used preparations
we have focused of the data of experimental studies carried out by other researchers on rats.
State of gastric mucous barrier was investigated by determination of composition of fractions of glycoproteins in suspension of gastric mucosa.
To perform biochemical studies animals have been decapitated by an one-stage in etherization, and recovered a stomach. Stomach was purified, irrigated with cold physiologic saline, proventriculus removed, mucous layer scraped out, weighted and suspended in physiologic salt solution at a rate of 30 mg/ml [10].
Composition of sialic acids in suspension was determined by a method of L. I. Linevik [11]. Results were expressed in mkg to ml of suspension.
To determine fucose in suspension of insoluble glycoprotein (IGP) was used a method proposed by P. D. Rabinovich et al. [12]. Results were expressed in mg to ml of suspension.
Content of protein was defined by O. H. Lowry et al. and expressed in mg to ml of suspension [13].
Data received were treated by using of Student's test by standard package Microsoft Excel.
Results and their discussion: Results of the studies conducted are given in the table.
№ Groups of animals Sialic acids mkg in ml of suspension Fucose Mg in ml of suspension Whole protein mg in ml of suspension
1. Control 4.12 ± 0.158 6.73 ± 0.125 15.22 ± 0.655
2. ERA 3.84 ± 0.155 6.25 ± 0.153 14.72 ± 0.593
3. GERA 1.22 ± 0.067 2.78 ± 0.100 7.65 ± 0.257
4. GERA+H20 1.38 ± 0.072 2.85 ± 0.121 8.55 ± 0.352
5. GE^A+enalapril 2.22 ± 0.047* 3.82 ± 0.089* 9.92 ± 0.400
6. GERA+lysinopril 2.47 ± 0.085* 4.12 ± 0.051* 10.12 ± 0.397*
7. GERA+captopril 3.27 ± 0.041* 4.82 ± 0.106* 11.75 ± 0.546*
8. GERA+omeprazole 3.52 ± 0.089* 4.12 ± 0.076* 10.22 ± 0.343*
9. GERA+misoprostol 3.92 ± 0.122* 5.32 ± 0.089* 12.32 ± 0.483*
Note: * - P<0,05 from index of GERA group without treatment (GERA+H20)
How it is shown from the data presented a composition of fractions of insoluble glycoproteins in ERA. was practically not changed.
Demonstrable reduction of fractions of insoluble glycoproteins was observed in animals with GERA. Content of sialic acids was lower than 69.5%, and that of fucose
and protein - 55.5% and 48.1% respectively from indicator in group of animals with ERA. (P < 0,001).
I-ACE, omeprazole and misoprostol had a positive effect on content of fractions of insoluble glycoproteins in gastric mucosa. An increase in composition of sialic acids by 60.8%, fucose - 34.5% and protein - 29.7% in
Table 1. - Content of fractions of insoluble glycoproteins in gastric mucosa in indometacin-induced gastropathy in animals with experimental rheumatoid arthritis. Effects of using of I-ACE, omeprazole and misoprostol
group treated with enalapril noted to be compared with group indices of animals with GERA without treatment. Nearly analogous results were observed in groups treated with lysinopril and omeprazole.
Application of captopril and misoprostol occurred to be more effective in treatment of GERA.. In group of animals treated with captopril a content of sialic acids was increased by 136.2%, fucose - 69.7% and protein - 37.4% from indicators in group without treatment. In treatment with misoprostol a content ofsialic acids was increased by 183.3%, fucose - 87.3% and protein - 44.1%.
It was established that sialic acids and fucose play a special role in full-grown functioning of glycoproteins. These carbohydrate components provide elasticity and viscosity of mucous barrier [14]. Results obtained in group of animals with GERA allow confirm that damage ofmucous barrier was caused by decrease of glycoproteins' synthesis and its functional insufficiency characterized by changes in its rheological features. In the literature available a negative effect ofindometacin on mucous barrier explains for inhibition of cyclooxygenase (COG) ferments, suppression of prostaglandins' production with the following microcirculation disturbance. It is supposed that this mechanism is not only one in this kind.
In the literature are available convincing data confirming an ulcer-healing effect of enalapril [15]. The authors unite this fact with stimulation of prostaglandins' synthesis. We assume that it is one of the mechanisms of positive effect of preparation that is consequence of correcting action of preparation on a system of NO-production. Mikheyeva O. M. et al. [2] in their clinico-experimental studies established an ulcer-healing effect of enalapril on defect of gastric mucous membrane in ulcer disease. The authors approve that this effect of enalapril is caused by improvement of microcirculation in gastric mucosa. Nikonov E. L. investigated effect of captopril and lysinopril on a state of gastric mucous membrane in patients with arterial hypertension and osteoarthritis over a long period of time taken NSAID [16]. The author established that I-ACE has positive effect on not only cardio-vascular system but also improve
morpho-functional indicators of gastric mucous membrane. S. A. Alexeyenko et al. [3] confirm that mechanisms of positive effect of preparations of I-ACE group on gastric mucosa require the subsequent research.
Among the I-ACE used by us the best cytoprotec-tive effect was observed in application of captopril. It is likely to cause by a presence of preparation of sulph-hydrile group in chemical structure. How it is known a sulphhydrile group is necessary for prostanoids' synthesis and activation of prostaglandins' receptors, it effects on membranes' permeability and interconnects free radicals. These assertions confirm results of studies of Nafeeza MohdIsmail et al. [4].
Positive effect of omeprazole on synthesis of insoluble glycoproteins and a number of the functioning mucus-producing cells was established by us. In the literature are available contradictory assumptions about cytoprotective effect of omeprazole. Chandranath S. I. et al. [17] establish that inhibitors of proton pomp (IPP) have cytoprotective effect owing to suppression of acidic aggression and perhaps owing to other unknown mechanisms. Watanabe T. et al. [17] assume that protective action of IPP on gastric mucous tissue in its disturbance with ethanol is accomplished through regulation of production system of nitrogen oxide, and meanwhile a number of prostaglandins were not changed.
How Abdulkhakov R. A. established cytotek similarly to endogen prostaglandins has an ability to increase mucus production and secretion of bicarbonates, perfect blood flow, stimulate regeneration of epithelium of gastric mucous membrane, and decrease production of hydrochloric acid [18].
Conclusions
1. Damage of gastric mucosa in indometacin-in-duced gastropathy is characterized by decrease ofcontent of carbohydrate and protein fractions of glycoproteins.
2. I-ACE - enalapril, lysinopril and captopril increase composition of glycoproteins in gastric mucosa. In this effect captopril excels enalapril and lysinopril.
3. In its cytoprotective effect captopril equates to misoprostol,
References:
1. Ahmedov V. A., Vinshegina V. A., Sudakova A. N. et al. Gastropathy caused by non-steroid anti-inflammatory drugs: from understanding mechanisms of development to elaboration of strategy of treatment and prevention. Therapeutical archives. - 2007. - No. 2. - P. 81-85.
STATE OF GASTRIC MUCOUS BARRIER IN INDOMETACIN-INDUCED GASTROPATHY EFFECTS...
2. Mikheyeva О. М., Lazebnik L. B., Belostotsky N. I. et al. Clinico-experimental substantiation of positive action of hypotensive preparations on defect of gastric mucous membrane in ulcer disease. Experimental & Clinical Gastroenterology. - 2007. - No. 5. - P 11-20.
3. Alexseyenko S. A., Timoshin S. S., Avilova А. А. et al. Effect of enalapril, lysinopril and amlodipin on a course of chronic gastritis in patients with arterial hypertension. Clinical Medicine. - 2004. - Volume 82. - No. 9. - P. 42-45.
4. Nafeeza Mohd Ismail, Ibrahim Abdel Aziz Ibrahim, NajihahM. B. et al. Effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions in Sprague-Dawley rats. ArchMedSci - 2012. - No. 1. -P. 1-6.
5. Meschischen I. F., Vasilyev S. V. Effect of indometacin and voltaren on oxidation and restoration of glutathione in liver of white rats // Pharmacology & Toxicology. - 1985. - No. 1. - P. 28-30.
6. Timoshin S. S. Involvement of neuropeptids in maintenance of tissue homeostasis of mucous membrane of gastrointestinal tract // Supplement № 14 to РЖГГК: materials of the XYIth session of the A. M. Ugolev Academic School-Seminar and contemporary problems of Physiology & Pathology of Digestion. - 2001. - No. 4. - P. 38-43.
7. Kovaleva М. V., Afonin VYu., Shilov V. V. et al. Evaluation of hypotensive effect and adverse action of generic preparation lysinopril // Materials of the Russian Scientific Conference with International Participation: Actual problems of Toxicology & Radiobiology, - Saint-Petersburg, 19-20 May - 2011. - P. 17.
8. Daminov Sh. N., Inoyatova F.Kh. Comparative evaluation of effects of quamatel and omez on glutathione system in different sections of digestive system in experimental duodenal ulcer // Experimental & Clinical Pharmacology. - 1998. - No. 4. - P. 26-28.
9. Halil Asci, Ozer M. K., Calapoglu M., Savran M., Oncu M., Yesilot S., Candan I. A., Kulac E., Cicek E. Effects of Misoprostol on Methotrexate-Induced Hepatic and Renal Damages // Journal of Biology and Life Sciences. -2011. - Vol 2. - No. 1. - Р. 32-37.
10. Properties of gastric and duodenal mucus: Effect of protivolizis disulfide reduction, bibe, acid, ethanol and hyper-tonicity on mucus gel structure / A. E. Bell, L. A. Sellers, A. Allen, W.J. Cunliffe // Gastroenterol. - 1995. - Vol. 88. - No. 1. - P. 269-280.
11. Linevik L. I. Achievements of biological chemistry. - М., - 1962. - Т. 4. - 193 p.
12. Rabinovich P. D., Milyushkin P. V. Biologic oxidation and principal functions of stomach in ulcer patients // Therapeutical Archives. - 179. - No. 11. - P. 103-105.
13. Protein measurement with the folin phenol reagent / O. H. Lowry, N. J. Rosebrough, A. L. Farr, R.J. Randall // J. Biol.Chem. - 1951. - Vol. 193. - No. 1. - P. 265-275.
14. Khamrayev A. A. Peculiarities of disturbances of gastric mucosal barrier in presence of Helicobacter pylori in patients with duodenal ulcer // AikapcbKa справа. - 2005. - No. 7. - P. 34-36.
15. Smirnova L. About problem of co-morbidity of ulcerous erosive disorders of gastroduodenal zone and arterial hypertension // Clinical Medicine. - 2003. - No. 5. - P. 9-15.
16. Nikonov Е. L. Effect of antihypertensive therapy on state of gastric ucosal membrane in patients with arterial hypertension and osteoarthritis prolonged taken non-steroid anti-inflammatory drugs (NSAID) // The Russian Journal of Gastroenterology & Hepatology & Coloproctology. - 2001. - No. 5. - 49 p.
17. Cytoprotective effect of rabeprazole against ethanol-induced gastric mucosal damage: possible involvement of nitric oxide / Watanabe T., Higuchi K., Tominaga K. et al. // Drugs Exp Clin Res., - 2000. - Vol. 26 (2). - P. 41-45.
18. Abdulkhakov R. A. Modern principles of treatment of ulcer disease // The Kazan Medical Journal. - 2002. -Volume 83. - No. 3. - P. 233-235.
