Cytoprotective processes induced by the effect of L-arginin-L-glutamate in rats with experimental pathology of the gastroduodenal zone


The processes of effect of L-arginine-L-glutamate on peroxidation and slime-forming function of the stomach cells, the system of antioxidant defense in the blood, liver and brain tissues of rats with experimental pathology of the gastroduodenal zone have been investigated. The animals were divided into four groups. Group I – control group were rats injected intragastrically through a probe physiological solution. Group II included animals with erosive ulcerative lesions of the gastroduodenal zone. Modeling of the erosive ulcerative lesions was carried out by intragastric administration of medical bile (1 ml/100 g) in combination with immobilization-cold stress for 1 hour at + 4 ºС for a period of seven days. Rats of group ІІІ simultaneously received an intra-abdominal 4% solution of L-arginine-L-glutamate in a dose of 20 mg per 100 g of body weight at the same time as the erosive ulcerative lesions modeling. To clarify the role of NO-ergic mechanism of L-arginine-L-glutamate influence on the quantitative composition of mucins and free radical processes rats in group ІV with erosive ulcerative lesions were injected with non-selective NO-synthase inhibitor, L-NAME (L-NG-nitroarginine methyl ester), at a dose of 1 mg per 100 g at the same time as injections of 4% solution of L-arginine-L-glutamate. The simulation of erosive-ulcerative lesions of the gastroduodenal zone in the experimental animals was accompanied by the intensification of lipid peroxidation processes, the imbalance of the antioxidant defense systems and the development of oxidative stress in the blood, tissues of the stomach, liver and brain, which has tissue-specific features. In the blood of the animals, the activation of the enzymatic link of antioxidant defense did not compensate for free radical processes, as a result, the exhaustion of the reduced glutathione pool occurred, and the level of TBA-active products increased both in plasma and in erythrocytes. There was a depression of the enzymes of the antioxidant defense and a decrease in the level of recovered glutathione, indicating decompensating of the liver antioxidant protection systems in the liver tissue of the rats. In the experimental animals , formation of erosive ulcerative lesions was accompanied by destabilization of the oxidation-reducing processes in the brain, which led to the intensification of the lipoperoxidation. In the mucous membrane of the stomach of the experimental animals, the total number of protection factors – secretory mucins with a simultaneous structural change – decreased. The use of L-arginine-L-glutamate reduced the manifestations of oxidative stress in the stomach tissue of animals with experimental pathology and normalized the quantitative and qualitative composition of mucins. In the blood, liver tissues and brain of the rats, L-arginine-L-glutamate injections activated the enzymes of the first anti-radical linkage – superoxide dismutase and catalase contributed to the increase of the pool of reduced glutathione and the deceleration of free radical reactions. Investigation of reactions to the action of the inhibitor provides the basis for the hypothesis of the NO-mediated action of L-arginine-L-glutamate on the formation of S-nitrosothiols, as evidenced by the high level of reduced glutathione when the inhibitor is used.


Amagase, K., Nakamura, E., Kato, S., & Takeuchi, K. (2015). Glutamate as a potential protective drug in the gastrointestinal mucosa. Yakugaku Zasshi, 135(6), 779–782.

Babak, O. J., Frolov, V. M., & Harchenko, N. V. (2005). Glutargin – farmakologicheskoe dejstvie i klinicheskoe primenenie [Glutargin – pharmacological action and clinical application]. Jelton-2, Kharkov (in Russian).

Barinov, E. F., Kondratenko, P. G., Sulaeva, O. N., Jarikov, S. O., & Delyy, V. Y. (2013). Gastrointestinal'nyy bar'yer: Strukturnyye i molekulyarnyye determinanty v norme i pri ul'tserogeneze [Gastrointestinal barrier: Structural and molecular determinants in norm and in ulcerogenesis]. Ukrayinskyy Zhurnal Khirurhiyi, 23(4), 96–104 (in Russian).

Bhattacharyya, A., Chattopadhyay, R., Mitra, S., & Crowe, S. E. (2014). Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiological Reviews, 94(2), 329–354.

Broniowska, K. A., Diers, A. R., & Hogg, N. (2013). S-nitrosoglutathione. Biochimica Biophysica Acta, 1830(5), 3173–3181.

Chen, Y., Dong, H., Thompson, D. C., Shertzer, H. G., Nebert, D. W., & Vasiliou, V. (2013). Glutathione defense mechanism in liver injury: Insights from animal models. Food and Chemical Toxicology, 60, 38–44.

Cossenza, M., Socodato, R. C., Portugal, C. C., Domith, I. C., Gladulich, L. F., Encarnação, T. G., Calaza, K. C., Mendonça, H. R., Campello-Costa, P., & Paes-de-Carvalho, R. (2014). Nitric oxide in the nervous system: Biochemical, developmental, and neurobiological aspects. Vitamins and Hormones, 96, 79–125.

Duarte, H. O., Freitas, D., Gomes, C., Gomes, J., Magalhães, A., & Reis, C. (2016). Mucin-type O-glycosylation in gastric carcinogenesis. Biomolecules, 6(3), 33.

El-Demerdash, E., El-Mesallamy, H. O., Abu-Zaid, N. M., & Gad, M. Z. (2010). The potential therapeutic effect of nitric oxide modulators in experimentally-induced gastric ulcers. Drug Discoveries and Therapeutics, 4(4), 276–284.

Gyires, K., Toth, V. E., & Zadori, Z. S. (2015). Gastric mucosal protection: From the periphery to the central nervous system. Jornal of Physiology and Pharmacolology, 66(3), 319–329.

Hlynov, I. B., & Chikunova, M. V. (2016). Znacheniye slizisto-bikarbonatnogo bar'yera zheludka pri kislotnozavisimykh zabolevaniyakh [The role of gastric mucus-bicarbonate barrier in acid diseases]. Russkij Medicinskij Zhurnal, 17, 1125–1129 (in Russian).

Ishibashi-Shiraishi, I., Shiraishi, S., Fujita, S., Ogawa, S., Kaneko, M., Suzuki, M., & Tanaka, T. (2016). L-arginine L-glutamate enhances gastric motor function in rats and dogs and improves delayed gastric emptying in dogs. Journal of Pharmacology and Experimental Therapeutics, 359(2), 238–246.

Jiménez, M. D., Martín, M. J., Alarcón de la Lastra, C., Bruseghini, L., Esteras, A., Herrerías, J. M., & Motilva, V. (2004). Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa. Free Radical Research, 38(9), 903–911.

Keszler, A., Zhang, Y., & Hogg, N. (2010). Reaction between nitric oxide, glutathione, and oxygen in the presence and absence of protein: How are S-nitrosothiols formed? Free Radical Biology and Medicine, 48(1), 55–64.

Kim, S. F. (2014). The nitric oxide-mediated regulation of prostaglandin signaling in medicine. Vitamins and Hormones, 96, 211–245.

Kirichuk, V. F., Andronov, E. V., Ivanov, A. N., & Mamontova, N. V. (2008). Oksid azota i mikrocirkuljatornoe zveno sistemy gemostaza (obzor literatury) [Nitric oxide and microcirculatory unit of the hemostasis system (literature review)]. Uspehi Fiziologicheskih Nauk, 39(4), 83–91 (in Russian).

Kolesnik, B., Palten, K., Schrammel, A., Stessel, H., Schmidt, K., Mayer, B., & Gorren, A. C. (2013). Efficient nitrosation of glutathione by nitric oxide. Free Radical Biology and Medicine, 63, 51–64.

Kulinskij, V. I., & Kolesnichenko, L. S. (2009). Sistema glutationa. І. Sintez, transport, glutationtransferazy, glutationperoksidazy [Glutathione system. І. Synthesis, transport, glutathione transferase, glutathione peroxidase]. Biomedicinskaja Himija, 55(3), 255–277 (in Russian).

Kumar, S., Singh, R. K., & Bhardwaj, T. R. (2017). Therapeutic role of nitric oxide as emerging molecule. Biomedicine and Pharmacotherapy, 85(1), 182–201.

Kunio, T., Hisayuki, U., & Eiji, N. (2013). Physiological roles of dietary glutamate signaling via gut-brain axis due to efficient digestion and absorption. Journal of Gastroenterology, 48(4), 442–451.

Kwiecien, S., Jasnos, K., Magierowski, M., Sliwowski, Z., Pajdo, R., Brzozowski, B., Mach, T., Wojcik, D., & Brzozowski, T. (2014). Lipid peroxidation, reactive oxygen species and antioxidative factors in the pathogenesis of gastric mucosal lesions and mechanism of protection against oxidative stress-induced gastric injury. Journal of Physiology and Pharmacology, 65(5), 613–622.

Larsson, J. M., Thomsson, K. A., Rodríguez-Piñeiro, A. M., Karlsson, H., & Hansson, G. C. (2013). Studies of mucus in mouse stomach, small intestine, and colon. III. Gastrointestinal Muc5ac and Muc2 mucin O-glycan patterns reveal a regiospecific distribution. American Journal of Physiology – Gastrointestinal and Liver Physiology, 305(5), 357–363.

Lei, J., Vodovotz, Y., Tzeng, E., & Billiar, T. R. (2013). Nitric oxide, a protective molecule in the cardiovascular system. Nitric Oxide, 35, 175–185.

Li, S, Tan, H. Y., Wang, N., Zhang, Z. J., Lao, L., Wong, C. W., & Feng, Y. (2015). The role of oxidative stress and antioxidants in liver diseases. International Journal of Molecular Sciences, 16(11), 26087–26124.

Lundberg, J. O., & Weitzberg, E. (2012). Biology of nitrogen oxides in the gastrointestinal tract. Gut, 62(4), 616–629.

Lykholat, T., Lykholat, O., & Antonyuk, S. (2016). Immunohistochemical and biochemical analysis of mammary gland tumours of different age patients. Cytology and Genetic, 50(1), 32–41.

Lykholat, O. A., Grigoryuk, I. P., & Lykholat, T. Y. (2016). Metabolic effects of alimentary estrogen in different age animals. Annals of Agrarian Science, 14(4), 335–339.

Magierowski, M., Magierowska, K., Slawomir Kwiecien, S., & Brzozowski, T. (2015). Gaseous mediators nitric oxide and hydrogen sulfide in the mechanism of gastrointestinal integrity, protection and ulcer healing. Molecules, 20(5), 9099–9123.

Matsui, H., Nagano, Y., Shimokawa, O., Kaneko, T., Rai, K., Udo, J., Hirayama, A., Nakamura, Y., Indo, H. P., Majima, H. J., & Hyodo, I. (2011). Gastric acid induces mitochondrial superoxide production and lipid peroxidation in gastric epithelial cells. Journal of Gastroenterology, 46(10), 1167–1176.

Mohanty, J. G., Nagababu, E., & Rifkind, J. M. (2014). Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging. Frontiers in Physiology, 28(5), 84.

Ovsjannikova, M. M., Al'ohіna, S. M., & Drobіns'ka, O. V. (1999). Bіohіmіchnі ta bіofіzichnі metodi ocіnki porushen' okisljuval'nogo gomeostazu v osіb, shho zaznali radіacіjnogo vplivu vnaslіdok avarії na ChAES [Biochemical and biophysical methods for evaluating the disturbances of oxidative homeostasis in persons who have undergone radiation influence as a result of the Chernobyl accident]. Kyiv (in Russian).

Pen, X., Zou, L., Zhang, X., Branco, V., Wang, J., Carvalho, C., Holmgren, A., & Lu, J. (2017). Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxidants and Redox Signaling, 27(13), 989–1010.

Pereslegina, I. A. (1989). Aktivnost' antioksidantnyh fermentov sljuny u zdorovyh detej [Activity of antioxidant saliva enzymes in healthy children]. Laboratornoe Delo, 11, 20–23 (in Russian).

Pérez, S., Taléns-Visconti, R., Rius-Pérez, S., Finamor, I., & Sastre, J. (2017). Redox signaling in the gastrointestinal tract. Free Radical Biology and Medicine, 104, 75–103.

Robaczewska, J., Kedziora-Kornatowska, K., Kozakiewicz, M., Zary-Sikorska, E., Pawluk, H., Pawliszak, W., & Kedziora, J. (2016). Role of glutathione metabolism and glutathione-related antioxidant defense systems in hypertension. Jornal of Physiology and Pharmacology, 67(3), 331–337.

Prohorova, M. I. (Ed.). (1982). Metody biohimicheskih issledovanij (lipidnyj i jenergeticheskij obmen) [Methods of biochemical research (lipid and energy metabolism)]. Leningradskij Universitetet, Leningrad (in Russian).

Rudenko, A. І., Majkova, T. V., Mosіjchuk, L. M., Ponomarenko, O. A., Tolstіkova, T. M., & Sirotenko, A. S. (2004). Klіnіko-laboratorna ocіnka funkcіonal'nogo stanu sekretornih zaloz shlunka [Clinical and laboratory evaluation of functional state of the secretory glands of the stomach]. Kyiv (in Russian).

Semenchuk, S. A., Jakovleva, O. A., & Stockaja, T. V. (2017). Jeffektivnost' primenenija L-arginina-L-glutamata kak metabolicheskogo korrektora u bol'nyh s postinfarktnym kardiosklerozom [The efficacy of L-arginine-L-glutamate as a metabolic corrector in patients with postinfarction cardiosclerosis]. Bukovyns'kyj Medychnyj Visnyk, 21(1), 132–135 (in Russian).

Sgambato, D., Capuano, A., Sullo, M. G., Miranda, A., Federico, A., & Romano, M. (2016). Gut-brain axis in gastric mucosal damage and protection. Current Neuropharmacology, 14(8), 959–966.

Sulaeva, O. N. (2015). Strukturnaja organizacija i fiziologicheskie jeffekty bluzhdajushhego nerva v ZhK [Structural organization and physiological effects of the vagus nerve in the GIT]. Svit Medycyny ta Biologiyi, 53(4), 164–171 (in Russian).

Shelly, C., & Lu, M. D. (2013). Glutathione synthesis. Biochimica et Biophysica Acta, 1830(5), 3143–3153.

Taché, Y. (2012). Brainstem neuropeptides and vagal protection of the gastric mucosal against injury: Role of prostaglandins, nitric oxide and calcitonin-gene related peptide in capsaicin afferents. Current Medicinal Chemistry, 19(1), 35–42.

Tarasenko, L. M., Neporada, K. S., Skrypnik, I. N., & Volozhin, A. I. (2001). Jeksperimental'naja model' pepticheskoj jazvy zheludka [Experimental model of peptic ulcer of the stomach]. Patologicheskaja Fiziologija i Jeksperimental'naja Medicina, 1, 27–28 (in Russian).

Tarnawski, A. S., Ahluwalia, A., & Jones, M. K. (2012). The mechanisms of gastric mucosal injury: Focus on microvascular endothelium as a key target. Current Medicinal Chemistry, 19(1), 4–15.

Tkach, S. M., Puchkov, K. S., & Kuzenko, Y. G. (2013). Biologicheskiye effekty oksidov azota v zheludochno kishechnom trakte [Biological effects of nitric oxide in the gastrointestinal tract]. Suchasna Gastroyenterologíya, 72(4), 118–128 (in Russian).

van Zwieten, R., Verhoeven, A. J., & Roos, D. (2014). Inborn defects in the antioxidant systems of human red blood cells. Free Radical Biology and Medicine, 67(2), 377–386.

Wallace, J. L., Ianaro, A., & de Nucci, G. (2017). Gaseous mediators in gastrointestinal mucosal defense and injury. Digestive Diseases and Sciences, 62(9), 2223–2230.

Wu, G. (1998). Intestinal mucosal amino acid catabolism. Jornal of Nutrition, 128(8), 1249–1252.

Yandrapu, H., & Sarosiek, J. (2015). Protective factors of the gastric and duodenal mucosa: An overview. Current Gastroenterology Reports, 17(6), 24.

Yermishev, O., Lykholat, T., & Lykholat, O. (2017). Effect of alimentary synthetic estrogen on cell compensatory mechanisms in rats of different ages. Biologia, 63(2), 152–159.

Zolotarev, V. A., Andreeva, Y. V., Vershinina, E., & Khropycheva, R. P. (2017). Interaction of constitutive nitric oxide synthases with cyclooxygenases in regulation of bicarbonate secretion in the gastric mucosa. Bulletin of Experimental Biology and Medicine, 163(1), 6–9.

Zolotova, N. A. (2014). Strukturnaya i funktsional'naya kharakteristika mutsinov [Structural and functional characteristics of mucins]. Klinicheskaya i funktsional'naya Morfologiya, 1, 66–72 (in Russian).

How to Cite
Stepanov, Y. M., Ponomarenko, L. A., Lykholat, O. A., Shevchenko, T. M., Khomenko, O. M., & Ponomarenko, A. A. (2018). Cytoprotective processes induced by the effect of L-arginin-L-glutamate in rats with experimental pathology of the gastroduodenal zone. Regulatory Mechanisms in Biosystems, 9(2), 300-307.