Sklyarova Yu. O., Fomenko I. S.

CLINICAL AND EXPERIMENTAL MEDICINE

Scentific article

Small intestinal injury is known to be one of the most commonly appearing pathologies, resulting in the use of medications such as: nonsteroidal anti-inflammatory drugs (NSAIDs), antitumor drugs and angiotensinconverting enzyme (ACE) inhibitors. ACE inhibitors induce bowel angioedema, manifested in patients as abruptonset abdominal pain and nausea, with vomiting and sometimes diarrhea. The principal objective of this study was to evaluate the action of a H2S donors NaHS at doses 1 and 10 mg/kg and L-cysteine at a dose 30 mg/kg on parameters of NO-synthase system and oxidative stress in small intestine of rats under condition of enalapril an ACE inhibitor (2 mg/kg/day) enterotoxic action. The structure of this study and the experimental procedures performed on the animals were approved by the Ethical Committee of Lviv National Medical University. The experimental procedures were carried out in accordance with the international guidelines for the use and care of laboratory animals. Male, outbred albino rats weighing 200–220 g were used. Enalapril, an ACE inhibitor was introduced three times in a dose 2mg/kg/day to induce enteropathy. H2S donors NaHS at doses 1 and 10 mg/kg and L-cysteine at a dose 30 mg/kg were used for the correction of enterotoxic enalapril action. In the mucosa of small intestine were determined: malonic dialdehyde (MDA) concentration, activity of myeloperoxydase (MPO), superoxide dismutase (SOD), catalase, NO-synthases (NOS). It was shown that the introduction of enalapril didn’t cause any visible changes of the small intestine surface, however led to activation of myeloperoxidase, indicating inflammatory process, the increase of lipid peroxidation processes intensity manifested by the rise of MDA concentration and the decrease of catalase activity. All this together make special preconditions leading to the development of oxidative stress in small intestine and enteropathia formation. Inhibition of agiotensine-converting enzyme led to the decrease of activity of constitutive NO-synthase and arginase. Introduction of NaHS at doses 1 and 10 mg/kg at the background of enalapril action caused to the significant decrease of MPO activity, increase of activity of the constitutive NOsynthase and arginase. L-cystein decreased MDA concentration and the activity of catalase, however didn’t act on MPO activity. Received results on the one hand show that H2S released was involved in mechanisms cytoprotection in small intestine on the other hand prove the relationship between metabolism of gaseous mediators: hydrogen sulfide and nitric oxide.

enteropathy, angiotensin-converting enzyme inhibitors, lipid peroxidation, nitric oxide, hydrogen sulfide, small intestinal mucosa

1. Sklyarova Y, Fomenko I, Lozynska I, Lozynskyi A, Lesyk R, Sklyarov A. Hydrogen sulfide releasing 2-mercaptoacrylic acid-based derivative possesses cytoprotective activity in a small intestine of rats with medication-induced enteropathy. Sci Pharm. 2017;85(4).
2. McGettigan MJ, Menias СO, Gao ZJ, Mellnick VM. Hara AK. Imaging of drug-induced complications in the gastrointestinal system. Radiographics. 2016;36:71-83.
3. Pusztaszeri MP, Genta RM, Cryer BL. Drug-induced injury in the gastrointestinal tract: Clinical and pathologic considerations. Nat. Clin. Pract. Gastroenterol. Hepatol. 2007;4(8):442-53.
4. Wilin KL, Czupryn MJ, Mui R, Renno A, Murphy JA. ACE Inhibitor-induced angioedema of the small bowel: a case report and review of the literature. J Pharm Pract. 2018;31(1):99-103.
5. Benson BC, Smith C, Laczek JT. Angiotensin converting enzyme inhibitor-induced gastrointestinal angioedema: a case series and literature review. J Clin Gastroenterol. 2013;47(10):844-9.
6. Perlot T, Penninger JM. ACE2 – from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect. 2013;15(13):866-73.
7. Aihara E, Kagawa S, Hayashi M, Takeuchi K. ACE inhibitor and AT1 antagonist stimulate duodenal HCO3- secretion mediated by a common pathway – involvement of PG, NO and bradykinin. J Physiol Pharmacol. 2005;56(3):391-406.
8. Sklyarova U, Denysenko N, Ilkiv I, Fomenko I. Tsytoprotektyvna dja donoriv hidrogenu sul’fidu v slyzovij obolontsi tonkoi kyshky za indometatsyn-enteropatij u shchuriv. Eksperimental’na ta klinichna fisiologia ta biohimia. 2017;77(1):38-44. [in Ukrainian].
9. Wang W, Xiao W, Sun L, Zhang C, Chen G, Yang H. Inhibition of ACE activity contributes to the intestinal structural compensation in a massive intestinal resection rat model. Pediatr. Surg. Int. 2012;28:533-54.
10. Timirbulatov RA, Seleznev EI. Metod povyshenia svobodnoradikal’nogo okislenia lipidosoderzhashchih komponentov krovi i ego diagnosticheskoe znachenie. Laboratornoe delo. 1981;4:209-17. [in Russian].
11. Bradley PP, Christensen RD, Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood. 1982;60:618-22.
12. Chevari S, Andyal T, Shtrenger Ya. Opredelenie antioksidantnyh parametrov krovi i ih diagnosticheskoe znachenie v pozhylom vozraste. Laboratornoe delo. 1991;10:9-13. [in Russian].
13. Koroluk M, Ivanova L, Mayorova I, Tokorev W. Metod opredelenia aktivnosti katalazy. Laboratornoe delo. 1988;1:16-9. [in Russian].
14. Ravaeva MY, Chuyan EN. Izmemenie aktivnosti sistemy oksida azota pod dejstviem nizkointensivnogo izluchenia. Uchenye Zapiski Tavricheskogo Natsional’nogo Universiteta im VI Vernadskogo Seriya Biologiya Himiya. 2011;24:201-10. [in Russian].
15. Geyer JW, Dabich D. Rapid method for determination of arginase activity in tissue homogenates. Anal. Biochem. 1971:30(2):412-7.
16. Mikrut K, Kupsz J, Kozlik J, Krauss H, Pruszynska-Oszmałek E, Gibas-Dorna M. Angiotensin-converting enzyme inhibitors reduce oxidative stress intensity in hyperglicemic conditions in rats independently from bradykinin receptor inhibitors. Croat Med J. 2016;31;57(4):371-80.
17. Chandran G, Sirajudeen KN, Yusoff NS, Swamy M, Samarendra MS. Effect of the antihypertensive drug enalapril on oxidative stress markers and antioxidant enzymes in kidney of spontaneously hypertensive rat. Oxid Med Cell Longev. 2014;2014:608512.
18. Denysenko N, Fedevych Yu, Sklyarov A. Modeluvannja aktyvnosti NO-syntaznoi systemy hydrogen sulfidom natriu u slysovij obolontsi tovstoj kyshky shchuriv za umov kolity. Visnyk L’vivs’kogo Universytetu. Seria Biologichna. 2016;73:286-91. [in Ukrainian].
19. Sagach VF, Baziljuk OV, Stepanenko LG, Korkach JuP, Kotsuruba AV. Vplyv enalaprylu na syntez oksydu azotu, okysnyj metabolism i tonus sudyn u staryh shchuriv. Fiziologichnyj jurnal. 2007;53(4):15-29. [in Ukrainian].
20. Fomenko I, Sklyarov A, Bondarchuk T, Biletska L, Panasyuk N, Wallace JL. Effects of conventional and hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs in rats with stress-induced and epinephrine-induced gastric damage. Stress. 2014;17(6):528-37.
21. Fomenko I, Sklyarov A, Denysenko N, Hrycevych N, Dranitsyna A, Wallace J. Interactions between nitric oxide and hydrogen sulfide generating systems in gastric mucosa under condition of the combined action of stress and NDAIDs. J. Appl. Pharm. Sci. 2017;7:13-9.

«Bulletin of problems biology and medicine» Issue 3 (145), 2018 year, 172-176 pages, index UDK 612-08-092.9:615.225

10.29254/2077-4214-2018-3-1-145-172-176