Effect of Heparin on the Formation and Healing of Gastric Ulcers Induced by Acetic Acid Application on the Gastric Mucosa in Rats

A. L. Efimov; Ефимов А. Л.; D. S. Sakhno; Сахно Д. С.; B. V. Sigua; Сигуа Б. В.; N. I. Yarushkina; Ярушкина Н. И.; L. P. Filaretova; Филаретова Л. П.

doi:10.31857/S0869813923100047

Effect of Heparin on the Formation and Healing of Gastric Ulcers Induced by Acetic Acid Application on the Gastric Mucosa in Rats

作者: Efimov A.¹, Sakhno D.², Sigua B.¹, Yarushkina N.², Filaretova L.²
隶属关系:
1. Mechnikov North-Western State Medical University
2. Pavlov Institute of Physiology
期: 卷 109, 编号 10 (2023)
页面: 1398-1413
栏目: ЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИ
URL: https://journals.rcsi.science/0869-8139/article/view/232273
DOI: https://doi.org/10.31857/S0869813923100047
EDN: https://elibrary.ru/HHPSLS
ID: 232273

如何引用文章

全文:

开放存取

##reader.subscriptionAccessGranted##
受限制的访问

订阅存取

详细
作者简介
参考
补充文件
统计

详细

The key factor in maintaining the integrity of the gastric mucosa is its normal blood supply, respectively, the use of drugs that improve it, including through a positive effect on the rheological properties of blood, is in demand for the treatment of gastric ulcer. These drugs include the anticoagulant heparin. The aim of the work is to study the effect of heparin on the formation and healing of gastric ulcers induced by the application of 60% acetic acid to the gastric mucosa in rats, while assessing the possible risk of bleeding. After application of acetic acid (day 0), the area of gastric ulcers was assessed on the 4th day (formation of the ulcers) and the 7th day (healing of the ulcers). To assess the effect on ulcer formation, heparin (1000 IU/kg/day, subcutaneously) was administered from days 0 to 3, and on the healing from days 4 to 6 after acid application. To check for possible bleeding under the influence of heparin, the level of hemoglobin in the blood was tested before acid application (basal), on the 4th and 7th days after application. The degree of bleeding was assessed based on the relative decrease in hemoglobin levels. The administration of heparin led to a decrease in the average area of ulcers both on the 4th and on the 7th day compared with that in control rats (heparin vehicle). In control rats, both on the 4th and on the 7th day, the hemoglobin level was reduced compared to the corresponding basal level. Heparin had no effect on the hemoglobin level at day 4, but potentiated the decrease in mean hemoglobin level at day 7, increasing the number of animals having a greater relative decrease in hemoglobin level compared to the corresponding control group. Thus, heparin may have a gastroprotective effect, manifested both in the weakening of the formation of an ulcer and in the acceleration of its healing, however, there is a risk of bleeding when the ulcer heals.

关键词

gastric ulcer, gastroprotection, heparin, anticoagulant, bleeding, rat

参考

Затевахин ИИ (2016) Абдоминальная хирургия. Национальное руководство: краткое издание. М. ГЭОТАР-Медиа [Zatevakhin AI (2016) Abdominal surgery. National Guide: Short Edition. M. GEOTAR-Media. (In Russ)].
Shim YK, Kim N (2016) Nonsteroidal anti-inflammatory drug and aspirin-induced peptic ulcer disease. Korean J Gastroenterol 67: 300–312. https://doi.org/10.4166/KJG.2016.67.6.300
Steadman CJ, Day RO, Henry DA, Muirden KD, Yeomans ND, Brooks PM, Stiel D, Prichard PJ (1992) Prophylaxis against NSAID-induced ulcers. Med J Aust 157: 801–803. https://doi.org/10.5694/J.1326-5377.1992.TB141292.X
Isaacs P (1996) Misoprostol and NSAID ulcers. Am J Gastroenterology 91(2): 187–188.
Teixeira DF, Santos AM, Oliveira AMS, Nascimento Júnior JAC, Frank LA, Santana Souza MT De, Camargo EA, Serafini MR (2021) Pharmaceuticals agents for preventing NSAID-induced gastric ulcers: a patent review. Expert Rev Clin Pharmacol 14: 677–686. https://doi.org/10.1080/17512433.2021.1909475
Rahman K, Ali G, Khan R, Khan I, Ali I, Mosa OF, Ahmed A, Ayaz M, Nawaz A, Murthy HCA (2022) Analagesic and anti-Inflammatory potentials of a less ulcerogenic thiadiazinethione derivative in animal models: biochemical and histochemical correlates. Drug Des Devel Ther 16: 1143–1157. https://doi.org/10.2147/DDDT.S354779
Filaretova L (2013) Gastroprotective role of glucocorticoids during NSAID-induced gastropathy. Curr Pharm Des 19: 29–33.
Levenstein S (2000) The very model of a modern etiology: a biopsychosocial view of peptic ulcer. Psychosom Med 62: 176–185. https://doi.org/10.1097/00006842-200003000-00003
Jones MP (2006) The role of psychosocial factors in peptic ulcer disease: beyond Helicobacter pylori and NSAIDs. J Psychosom Res 60: 407–412. https://doi.org/10.1016/J.JPSYCHORES.2005.08.009
Realo A, Teras A, Kööts-Ausmees L, Esko T, Metspalu A, Allik J (2015) The relationship between the Five-Factor Model personality traits and peptic ulcer disease in a large population-based adult sample. Scand J Psychol 56: 693–699. https://doi.org/10.1111/SJOP.12248
Goodwin CM, Hoffman JA (2011) Deep vein thrombosis and stress ulcer prophylaxis in the intensive care unit. J Pharm Pract 24: 78–88. https://doi.org/10.1177/0897190010393851
Clarke K, Adler N, Agrawal D, Bhakta D, Sata SS, Singh S, Gupta A, Pahwa A, Pherson E, Sun A, Volpicelli F, Cho HJ (2022) Indications for the Use of Proton Pump Inhibitors for Stress Ulcer Prophylaxis and Peptic Ulcer Bleeding in Hospitalized Patients. Am J Med 135: 313–317. https://doi.org/10.1016/J.AMJMED.2021.09.010
Гельфанд БР (2006) Профилактика стресс-повреждений желудочно-кишечного тракта у больных в критическом состоянии. В кн: Сепсис в начале ХХI века. М. Литтерра. 124–138. [Gel’fand BR (2006) Prevention of stress damage to the gastrointestinal tract in patients in critical condition.In: Sepsis at the beginning of the 21st century. M. Litterra. 124–138. (In Russ)].
Rafinazari N, Abbasi S, Farsaei S, Mansourian M, Adibi P (2016) Adherence to stress-related mucosal damage prophylaxis guideline in patients admitted to the Intensive Care Unit. J Res Pharm Pract 5: 186. https://doi.org/10.4103/2279-042X.185728
Bardou M, Quenot JP, Barkun A (2015) Stress-related mucosal disease in the critically ill patient. Nat Rev Gastroenterol Hepatol 12: 98–107. https://doi.org/10.1038/nrgastro.2014.235
Соколова ОВ (2012) Стрессовые повреждения желудочно-кишечного тракта при синдроме полиорганной недостаточности у реаниматологических больных. Вестник Нац мед-хирург Центра им НИ Пирогова 7(2): 115–121. [Sokolova OV (2012) Stress damage to the gastrointestinal tract in multiple organ failure syndrome in intensive care patients. Bull Nation Med Surgeon Pirogov Center 7(2): 115–121. (In Russ)].
Ohmann C, Imhof M, Röher HD (2000) Trends in peptic ulcer bleeding and surgical treatment. World J Surg 24: 284–293. https://doi.org/10.1007/S002689910046
Wilcox CM, Spenney JG (1988) Stress ulcer prophylaxis in medical patients: who, what, and how much? Am J Gastroenterol 83(11): 1199–1211.
Filaretova LP, Podvigina TT, Bobryshev PY, Bagaeva TR, Tanaka A, Takeuchi K (2006) Hypothalamic-pituitary-adrenocortical axis: The hidden gold in gastric mucosal homeostasis. Inflammopharmacology 14: 207–213. https://doi.org/10.1007/s10787-006-1544-2
Abdel-Salam OME, Czimmer J, Debreceni A, Szolcsányi J, Mózsik G (2001) Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview. J Physiol Paris 95: 105–127. https://doi.org/10.1016/S0928-4257(01)00015-8
Akimoto M, Hashimoto H, Shigemoto M, Yokoyama I (1998) Relationship between recurrence of gastric ulcer and the microcirculation. J Cardiovasc Pharmacol 31 Suppl 1: S507–S508. https://doi.org/10.1097/00005344-199800001-00145
Kalia N, Bardhan KD (2003) Of blood and guts: association between Helicobacter pylori and the gastric microcirculation. J Gastroenterol Hepatol 18: 1010–1017. https://doi.org/10.1046/J.1440-1746.2003.03062.X
Filaretova LP, Maltcev N, Bogdanov A, Levkovich Y (1999) Role of gastric microcirculation in the gastroprotection by glucocorticoids released during water-restraint stress in rats. Chin J Physiol 42: 145–152.
Heestermans M, Poenou G, Hamzeh-Cognasse H, Cognasse F, Bertoletti L (2022) Anticoagulants: A Short History, Their Mechanism of Action, Pharmacology, and Indications. Cells 11(20): 3214. https://doi.org/10.3390/cells11203214
Camporese G, Bernardi E (2009) Low-molecular-weight heparin for thromboprophylaxis. Curr Opin Pulm Med 15: 443–454. https://doi.org/10.1097/MCP.0B013E32832F5D9D
Venclauskas L, Llau JV, Jenny JY, Kjaersgaard-Andersen P, Jans Ø (2018) European guidelines on perioperative venous thromboembolism prophylaxis: Day surgery and fast-track surgery. Eur J Anaesthesiol 35: 134–138. https://doi.org/10.1097/EJA.0000000000000706
Кондашевская МВ (2022) Горизонты гепаринотерапии при COVID-19 и заболеваниях, связанных с пандемией. Роc физиол журн им ИМ Сеченова 108(4): 399–413. [Kondashevskaya MV (2022) Horizons of heparin therapy for COVID-19 and diseases associated with the pandemic. Russ J Physiol 108(4): 399–413. (In Russ)].
Billett HH, Reyes-Gil M, Szymanski J, Ikemura K, Stahl LR, Lo Y, Rahman S, Gonzalez-Lugo JD, Kushnir M, Barouqa M, Golestaneh L, Bellin E (2020) Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality. Thromb Haemost 120: 1691–1699. https://doi.org/10.1055/S-0040-1720978
Стилиди ИС, Сигуа БВ, Земляной ВП, Курков АА, Губков ИИ (2022) Рак желудка, осложненный кровотечением. (Систематический обзор литературы). Хирургия Журн им НИ Пирогова 6: 102–115. [Stilidi IS, Sigua BV, Zemlyanoj VP, Kurkov AA, Gubkov II (2022) Stomach cancer complicated by bleeding. (Systematic review of the literature). Hirurgiya Zhurn im NI Pirogova 6: 102–115. (In Russ)].
Земляной ВП, Климов СЕ, Сигуа БВ, Козобин АА, Козловская МГ (2016) Редкий случай кровотечения из острых язв тонкой кишки. Журн им НВ Склифосовского Неотложная мед помощь 4: 84−86. [Zemlyanoj VP, Klimov SE, Sigua BV, Kozobin AA, Kozlovskaya MG (2016) A rare case of bleeding from acute ulcers of the small intestine. Zhurn im NV Sklifosovskogo Neotlozhnaya med pomoshch 4: 84−86. (In Russ)].
Сигуа БВ, Земляной ВП, Губков ИИ, Данилов АМ, Сахно ДС, Захаров ЕА, Гуслев АБ (2018) Тактика хирургического лечения желудочных кровотечений опухолевого генеза у лиц пожилого и старческого возраста. Журн им НВ Склифосовского Неотложная мед помощь 2: 152−155. [Sigua BV, Zemlyanoj VP, Gubkov II, Danilov AM, Sahno DS, Zaharov EA, Guslev AB (2018) Tactics of surgical treatment of gastric bleeding of tumor origin in elderly and senile people. Zhurn im NV Sklifosovskogo Neotlozhnaya med pomoshch 2: 152−155. (In Russ)].
Филаретова ЛП (1990) Зависимость образования стрессорных язв желудка от состояния гипоталамо-гипофизарно-адренокортикальной системы. Физиол журн СССР им ИМ Сеченова 76(11): 1594–1600. [Filaretova L (1990) The dependence of the formation of stress stomach ulcers on the function of the hypothalamo-hypophyseal-adrenal cortical system. Russ J Physiol 76(11): 1594–1600. (In Russ)].
Filaretova LP, Filaretov AA, Makara GB (1998) Corticosterone increase inhibits stress-induced gastric erosions in rats. Am J Physiol 274: G1024–G1030.
Filaretova L (2017) Gastroprotective effect of stress preconditioning: involvement of glucocorticoids. Curr Pharm Des 23(27): 3923–3927. https://doi.org/10.2174/1381612823666170215145125
Filaretova L, Bagaeva T (2016) The Realization of the Brain-Gut Interactions with Corticotropin-Releasing Factor and Glucocorticoids. Curr Neuropharmacol 14: 876–881.
Filaretova L, Tanaka A, Miyazawa T, Kato S, Takeuchi K (2002) Mechanisms by which endogenous glucocorticoid protects against indomethacin-induced gastric injury in rats. Am J Physiol – Gastrointest Liver Physiol 283: 1082–1089. https://doi.org/10.1152/ajpgi.00189.2002
Filaretova L, Bagaeva T, Morozova O (2012) Stress and the stomach: Corticotropin-releasing factor may protect the gastric mucosa in stress through involvement of glucocorticoids. Cell Mol Neurobiol 32: 829–836. https://doi.org/10.1007/s10571-012-9800-z
Filaretova LP, Morozova OY, Yarushkina NI (2021) Peripheral corticotropin-releasing hormone may protect the gastric musosa against indometacin-induced injury through involvement of glucocorticoids. J Physiol Pharmacol 72: 1–10. https://doi.org/10.26402/JPP.2021.5.06
Filaretova L, Komkova O, Sudalina M, Yarushkina N (2021) Non-Invasive Remote Ischemic Preconditioning May Protect the Gastric Mucosa Against Ischemia-Reperfusion-Induced Injury Through Involvement of Glucocorticoids. Front Pharmacol 12. https://doi.org/10.3389/FPHAR.2021.682643
Filaretova LP, Morozova OYu (2022) From hypothalamic regulation of pituitary-adrenocortical axis to participation of glucocorticoids in gastroprotective action of corticotropin-releasing factor. J Evol Biochem Physiol 58(6): 1994–2006.
Tsukimi Y, Nozue C, Okabe S (1996) Effects of leminoprazole, omeprazole and sucralfate on indomethacin-induced delayed healing of kissing gastric ulcers in rats. J Gastroenterol Hepatol 11: 335–340. https://doi.org/10.1111/J.1440-1746.1996.TB01380.X
Filaretova L, Bagaeva T, Podvigina T (2002) Role of endogenous glucocorticoids in the healing of gastric erosions and chronic gastric ulcers in rats. Inflammopharmacology 10(4-6): 401–412.
Филаретова ЛП, Багаева ТР, Подвигина ТТ, Морозова ОЮ (2003) Недостаточная продукция глюкокортикоидов замедляет заживление острых эрозий и хронических язв слизистой оболочки желудка у крыс. Рос физиол журн им ИМ Сеченова 89(9): 1137–1146. [Filaretova LP, Bagaeva TR, Podvigina TT, Morozova OIu (2003) Deficiency of glucocorticoid production delays the healing of acute gastric mucosal erosion and chronic ulcers in rats. Russ J Physiol 89(9): 1137–1146. (In Russ)].
Kodama Y, Kumashiro R, Gain T, Matsumoto T (1983) The effect of heparin on stress ulcer formation in rats Am Surg 49(9): 506–510. https://pubmed.ncbi.nlm.nih.gov/6605103/
Li Y, Cho CH (1999) The ulcer healing effect of protamine sulphate in rat stomach. Aliment Pharmacol Ther 13: 1351–1362. https://doi.org/10.1046/J.1365-2036.1999.00618.X
Солнушкин СД, Чихман ВН (2018) Компьютерная обработка биологических изображений. Биомед. радиоэлектроника 2: 35–40. [Solnushkin SD, Chikhman VN (2018) Experience of biological images processing. Biomed. Radioengineer 2: 35–40. (In Russ)].
Magierowski M, Magierowska K, Surmiak M, Hubalewska-Mazgaj M, Kwiecien S, Wallace JL, Brzozowski T (2017) The effect of hydrogen sulfide-releasing naproxen (ATB-346) versus naproxen on formation of stress-induced gastric lesions, the regulation of systemic inflammation, hypoxia and alterations in gastric microcirculation. J Physiol Pharmacol 68(5): 749–756.
Филаретова ЛП, Левкович ЮИ, Филаретов АА (1995) Противоязвенное действие кортикостероидов обеспечивается за счет улучшения кровоснабжения желудка. Рос журн гастроэнтерологии гепатологии колопроктологии 5(3): 241–242. [Filaretova L, Levkovich Y, Filaretova AA The antiulcer effect of corticosteroids is provided by improving the blood supply to the stomach. Ross J Gastroenterol Hepatol Coloproctol 5(3): 241–242. (In Russ)].
Bobryshev P, Podvigina T, Maltcev N, Filaretova L (2006) Gastric microcirculation as target of gastroprotective action of glucocorticoid hormones in rats with desensitization of capsaicin-sensitive sensory neurons. Inflammopharmacology 14(5-6): 236–242. https://doi.org/10.1007/s10787-006-1546-0
Podvigina TT, Bobryshev PY, Bagaeva TR, Mal’tsev NA, Levkovich YI, Filaretova LP (2009) The effects of desensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach in rats depend on the blood glucocorticoid hormone level. Neurosci Behav Physiol 39: 559–564. https://doi.org/10.1007/s11055-009-9172-0
Kalayci M, Kocdor MA, Kuloglu T, Sahin İ, Sarac M, Aksoy A, Yardim M, Dalkilic S, Gursu O, Aydin S, Akkoc RF, Ugras M, Artas G, Ozercan İH, Ugur K, Aydin S (2017) Comparison of the therapeutic effects of sildenafil citrate, heparin and neuropeptides in a rat model of acetic acid-induced gastric ulcer. Life Sci 186: 102–110. https://doi.org/10.1016/J.LFS.2017.08.013
Li Y, Wang HY, Cho CH (1999) Association of heparin with basic fibroblast growth factor, epidermal growth factor, and constitutive nitric oxide synthase on healing of gastric ulcer in rats. J Pharmacol Exp Ther 290(2): 789–796.
Li Y, Wang WP, Wang HY, Cho CH (2000) Intragastric administration of heparin enhances gastric ulcer healing through a nitric oxide-dependent mechanism in rats. Eur J Pharmacol 399: 205–214. https://doi.org/10.1016/S0014-2999(00)00278-8
Горбашко АИ (1974) Острые желудочно-кишечные кровотечения. М. Медицина. [Gorbashko AI (1974) Acute gastrointestinal bleeding. M. Medicine. (In Russ)].