Ukr.Biochem.J. 2022; Volume 94, Issue 5, Sep-Oct, pp. 18-27


The level of nitric oxide and arginase activity in patients with arterial hypertension and diabetes mellitus during COVID-19

O. Y. Sklyarova1, S. R. Mahiiovych2, N. V. Denysenko3,
L. I. Kobylinska3*, Y. Y. Sklyarov2

1Department of Family Medicine FPGE, Danylo Halytsky Lviv National Medical University, Ukraine;
2Department of Therapy No 1 and Medical Diagnostics FPGE, Danylo Halytsky Lviv National Medical University, Ukraine;
3Department of Biological Chemistry, Danylo Halytsky Lviv National Medical University, Ukraine;

Received: 28 September 2022; Revised: 06 November 2022;
Accepted: 11 November 2022; Available on-line: 19 December 2022

The aim of this study was to assess the level of nitric oxide production and arginase activity in patients with arterial hypertension and type II diabetes mellitus during infection with SARS-CoV-2. The study groups included patients with arterial hypertension, patients with arterial hypertension combined with a severe course of COVID-19 and patients who, in addition to arterial hypertension and COVID-19, were suffering from type II diabetes mellitus. The volunteers without any clinical signs of diseases and normal blood pressure formed the control group. It has been established that arterial hypertension, combined with COVID-19 occurs along with reduced L-arginine, nitric oxide, superoxide dismutase activity and increased arginase activity. At the same time, the presence of arterial hypertension in patients with diabetes and coronavirus disease is accompanied by a decline in the content of L-arginine and arginase activity. Our study’s results may help scientists find new pharmacological targets in the future treatment of coronavirus disease and comorbid disorders.

Keywords: , , , , , ,


  1. Sanyaolu A, Okorie C, Marinkovic A, Patidar R, Younis K, Desai P, Hosein Z, Padda I, Mangat J, Altaf M. Comorbidity and its Impact on Patients with COVID-19. SN Compr Clin Med. 2020;2(8):1069-1076. PubMed, PubMedCentral, CrossRef
  2. Xu J, Xiao W, Liang X, Shi L, Zhang P, Wang Y, Wang Y, Yang H. A meta-analysis on the risk factors adjusted association between cardiovascular disease and COVID-19 severity. BMC Public Health. 2021;21(1):1533. PubMed, PubMedCentral, CrossRef
  3. Liu K, Chen Y, Lin R, Han K. Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients. J Infect. 2020;80(6):e14-e18. PubMed, PubMedCentral, CrossRef
  4. Zhao Q, Meng M, Kumar R, Wu Y, Huang J, Lian N, Deng Y, Lin S. The impact of COPD and smoking history on the severity of COVID-19: A systemic review and meta-analysis. J Med Virol. 2020;92(10):1915-1921. PubMed, PubMedCentral, CrossRef
  5. Zhang J, Wang X, Jia X, Li J, Hu K, Chen G, Wei J, Gong Z, Zhou C, Yu H, Yu M, Lei H, Cheng F, Zhang B, Xu Y, Wang G, Dong W. Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China. Clin Microbiol Infect. 2020;26(6):767-772. PubMed, PubMedCentral, CrossRef
  6. Samchuk OO, Kapustynska ОS, Sklyarov YeYa. Prevalence of some comorbid conditions at coronavirus disease. Clin Exp Pathol. 2021;20(4):66-73. (In Ukrainian). CrossRef
  7. Garg S, Kim L, Whitaker M, O’Halloran A, Cummings C, Holstein R, Prill M, Chai SJ, Kirley PD, Alden NB, Kawasaki B, Yousey-Hindes K, Niccolai L, Anderson EJ, Openo KP, Weigel A, Monroe ML, Ryan P, Henderson J, Kim S, Como-Sabetti K, Lynfield R, Sosin D, Torres S, Muse A, Bennett NM, Billing L, Sutton M, West N, Schaffner W, Talbot HK, Aquino C, George A, Budd A, Brammer L, Langley G, Hall AJ, Fry A. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 – COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464. PubMed, PubMedCentral, CrossRef
  8. Biswas M, Rahaman S, Biswas TK, Haque Z, Ibrahim B. Association of Sex, Age, and Comorbidities with Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis. Intervirology. 2020;1-12. PubMed, PubMedCentral, CrossRef
  9. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637. PubMed, PubMedCentral, CrossRef
  10. Zhang J, Xie B, Hashimoto K. Current status of potential therapeutic candidates for the COVID-19 crisis. Brain Behav Immun. 2020;87:59-73. PubMed, PubMedCentral, CrossRef
  11. Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies. Intern Emerg Med. 2020;15(5):759-766. PubMed, PubMedCentral, CrossRef
  12. Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res. 2020;43(7):648-654. PubMed, PubMedCentral, CrossRef
  13. Adebayo A, Varzideh F, Wilson S, Gambardella J, Eacobacci M, Jankauskas SS, Donkor K, Kansakar U, Trimarco V, Mone P, Lombardi A, Santulli G. l-Arginine and COVID-19: An Update. Nutrients. 2021;13(11):3951. PubMed, PubMedCentral, CrossRef
  14. Ricciardolo FLM, Bertolini F, Carriero V, Högman M. Nitric oxide’s physiologic effects and potential as a therapeutic agent against COVID-19. J Breath Res. 2020;15(1):014001. PubMed, CrossRef
  15. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical Features of 69 Cases With Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71(15):769-777. PubMed, PubMedCentral, CrossRef
  16. Clemente GS, van Waarde A, F Antunes IF, Dömling A, Elsinga PH. Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective. Int J Mol Sci. 2020;21(15):5291. PubMed, PubMedCentral, CrossRef
  17. Hosinian M, Qujeq D, Ahangar AA. The Relation Between GABA and L-Arginine Levels With Some Stroke Risk Factors in Acute Ischemic Stroke Patients. Int J Mol Cell Med. 2016;5(2):100-105. PubMed, PubMedCentral
  18. Bernardi F, Constantino L, Machado R, Petronilho F, Dal-Pizzol F. Plasma nitric oxide, endothelin-1, arginase and superoxide dismutase in pre-eclamptic women. J Obstet Gynaecol Res. 2008;34(6):957-963. PubMed, CrossRef
  19. Kiselyk IO, Lutsyk MD, Shevchenko LY. Peculiarities of nitrites and nitrates determination in peripheral blood in patients with viral hepatitis and jaundice syndrome of other etiology. Lab Diagnost. 2001;(3):43-45. (In Ukrainian).
  20. Hashmi MA, Ahsan B, Ali Shah SI, Khan MIU. Antioxidant Capacity and Lipid Peroxidation Product in Pulmonary Tuberculosis. Al Ameen J Med Sci. 2012; 5(3): 313-319.
  21. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W, Wang YN, Zhong MH, Li CH, Li GC, Liu HG. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020;133(9):1025-1031. PubMed, PubMedCentral, CrossRef
  22. Zhu B, Feng X, Jiang C, Mi S, Yang L, Zhao Z, Zhang Y, Zhang L. Correlation between white blood cell count at admission and mortality in COVID-19 patients: a retrospective study. BMC Infect Dis. 2021;21(1):574. PubMed, PubMedCentral, CrossRef
  23. Rees CA, Rostad CA, Mantus G, Anderson EJ, Chahroudi A, Jaggi P, Wrammert J, Ochoa JB, Ochoa A, Basu RK, Heilman S, Harris F, Lapp SA, Hussaini L, Vos MB, Brown LA, Morris CR. Altered amino acid profile in patients with SARS-CoV-2 infection. Proc Natl Acad Sci USA. 2021;118(25):e2101708118. PubMed, PubMedCentral, CrossRef
  24. Alamdari DH, Moghaddam AB, Amini S, Keramati MR, Zarmehri AM, Alamdari AH, Damsaz M, Banpour H, Yarahmadi A, Koliakos G. Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial. Eur J Pharmacol. 2020;885:173494. PubMed, PubMedCentral, CrossRef
  25. Durante W, Johnson FK, Johnson RA. Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol. 2007;34(9):906-911. PubMed, PubMedCentral, CrossRef
  26. Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program. 2008;177-185. PubMed, CrossRef
  27. Kоbylinska LI, Panchuk RR, Lesyk RB, Zіmenkovsky BS, Stoika RS. Indicators of oxidative and nitrosative stress and activity of enzymes of nitric oxide metabolism in rats treated with 4-thiazolidinone derivatives possessing antineoplastic activity. Ukr Biochem J. 2017;89(5):77-83. CrossRef
  28. Wu G, Morris SM Jr. Arginine metabolism: nitric oxide and beyond. Biochem J. 1998;336(Pt 1):1-17. PubMed, PubMedCentral, CrossRef
  29. Caldwell RW, Rodriguez PC, Toque HA, Narayanan SP, Caldwell RB. Arginase: A Multifaceted Enzyme Important in Health and Disease. Physiol Rev. 2018;98(2):641-665. PubMed, PubMedCentral, CrossRef
  30. Durante W. Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy. Metabolites. 2022;12(3):240. PubMed, PubMedCentral, CrossRef
  31. Kashyap SR, Lara A, Zhang R, Park YM, DeFronzo RA. Insulin reduces plasma arginase activity in type 2 diabetic patients. Diabetes Care. 2008;31(1):134-139. PubMed, PubMedCentral, CrossRef
  32. Grimes JM, Khan S, Badeaux M, Rao RM, Rowlinson SW, Carvajal RD. Arginine depletion as a therapeutic approach for patients with COVID-19. Int J Infect Dis. 2021;102:566-570. PubMed, PubMedCentral, CrossRef
  33. Ochoa JB, Bernard AC, O’Brien WE, Griffen MM, Maley ME, Rockich AK, Tsuei BJ, Boulanger BR, Kearney PA, Morris SM Jr. Arginase I expression and activity in human mononuclear cells after injury. Ann Surg. 2001;233(3):393-399. PubMed, PubMedCentral, CrossRef
  34. Ochoa JB, Bernard AC, Mistry SK, Morris SM Jr, Figert PL, Maley ME, Tsuei BJ, Boulanger BR, Kearney PA. Trauma increases extrahepatic arginase activity. Surgery. 2000;127(4):419-426. PubMed, PubMedCentral, CrossRef
  35. Renoux C, Fort R, Nader E, Boisson C, Joly P, Stauffer E, Robert M, Girard S, Cibiel A, Gauthier A, Connes P. Impact of COVID-19 on red blood cell rheology. Br J Haematol. 2021;192(4):e108-e111. PubMed, CrossRef
  36. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8. PubMed, PubMedCentral, CrossRef
  37. Wernly B, Pernow J, Kelm M, Jung C. The role of arginase in the microcirculation in cardiovascular disease. Clin Hemorheol Microcirc. 2020;74(1):79-92. PubMed, CrossRef
  38. Gambardella J, Khondkar W, Morelli MB, Wang X, Santulli G, Trimarco V. Arginine and Endothelial Function. Biomedicines. 2020;8(8):277. PubMed, PubMedCentral, CrossRef
  39. Tessari P, Cecchet D, Cosma A, Vettore M, Coracina A, Millioni R, Iori E, Puricelli L, Avogaro A, Vedovato M. Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy. Diabetes. 2010;59(9):2152-2159. PubMed, PubMedCentral, CrossRef
  40. Wang H, Wang AX, Aylor K, Barrett EJ. Nitric oxide directly promotes vascular endothelial insulin transport. Diabetes. 2013;62(12):4030-4042. PubMed, PubMedCentral, CrossRef
  41. Yaghoubi N, Youssefi M, Jabbari Azad F, Farzad F, Yavari Z, Zahedi Avval F. Total antioxidant capacity as a marker of severity of COVID-19 infection: Possible prognostic and therapeutic clinical application. J Med Virol. 2022;94(4):1558-1565. PubMed, PubMedCentral, CrossRef
  42. Delgado-Roche L, Mesta F. Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Arch Med Res. 2020;51(5):384-387. PubMed, PubMedCentral, CrossRef
  43. Kumar DS, Hanumanram G, Suthakaran PK, Mohanan J, Nair LDV, Rajendran K. Extracellular Oxidative Stress Markers in COVID-19 Patients with Diabetes as Co-Morbidity. Clin Pract. 2022;12(2):168-176. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.