farmaecFARMAKOEKONOMIKA. Modern Pharmacoeconomics and PharmacoepidemiologyФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология2070-49092070-4933IRBIS LLC10.17749/2070-4909/farmakoekonomika.2025.289farmaec-1146Research ArticleORIGINAL ARTICLESОРИГИНАЛЬНЫЕ ПУБЛИКАЦИИSystematic analysis of molecules regulating nitric oxide (NO) metabolism and vascular endothelium conditionСистематический анализ молекул, регулирующих обмен оксида азота (NO) и состояние сосудистого эндотелияhttps://orcid.org/0000-0002-2659-7998ТоршинИ. Ю.TorshinI. Yu.

Торшин Иван Юрьевич, к.ф-м.н., к.х.н.

WoS ResearcherID: C-7683-2018

Scopus Author ID: 7003300274

ул. Вавилова, д. 44, корп. 2, Москва 119333

Ivan Yu. Torshin, PhD (Phys. Math.), PhD (Chem.)

WoS ResearcherID: C-7683-2018

Scopus Author ID: 7003300274

44 corp. 2 Vavilov Str., Moscow 119333

https://orcid.org/0000-0002-5070-5450ЧучалинА. Г.ChuchalinA. G.

Чучалин Александр Григорьевич, д.м.н., проф., акад. РАН

ул. 1-я Леонова, д. 16, Москва 129226

Aleksandr G. Chuchalin, Dr. Sci. Med., Prof, Member of RAS 

16 1st Leonov Str., Moscow 129226

https://orcid.org/0000-0002-7663-710XГромоваО. А.GromovaO. A.

Громова Ольга Алексеевна, д.м.н., проф.

WoS ResearcherID: J-4946-2017

Scopus Author ID: 7003589812

ул. Вавилова, д. 44, корп. 2, Москва 119333

Olga A. Gromova, Dr. Sci. Med., Prof.

WoS ResearcherID: J-4946-2017

Scopus Author ID: 7003589812

44 corp. 2 Vavilov Str., Moscow 119333

unesco.gromova@gmail.comФедеральный исследовательский центр «Информатика и управление» Российской академии наукРоссияFederal Research Center “Computer Science and Control”, Russian Academy of SciencesRussian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Министерства здравоохранения Российской ФедерацииРоссияPirogov Russian National Research Medical UniversityRussian Federation2025020520251814260Copyright © Torshin I.Y., Chuchalin A.G., Gromova O.A., 20252025Торшин И.Ю., Чучалин А.Г., Громова О.А.Torshin I.Y., Chuchalin A.G., Gromova O.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmacoeconomics.ru/jour/article/view/1146Background

Background. Nitric monooxide (NO) is a signaling molecule that plays an important role in many physiological processes, including the regulation of vascular tone, neurotransmission, immunity, mitochondrial respiration, and skeletal muscle contractility. Certain molecules, which are micronutrients or active ingredients of a number of drugs, improve NO biosynthesis and secretion.

Objective

Objective: systematization of information on the impact of various molecules on the modulation of NO levels in normal and pathological conditions.

Material and methods

Material and methods. An array of all currently available publications on fundamental and clinical studies of the effects of various molecules on NO levels was studied. By the query “nitric oxide” in the PubMed/MEDLINE database of biomedical publications 198,480 articles were detected, and by the query “nitric oxide AND endothelium” 27,869 articles were found (with a peak in 2005). After loading this sample, a systematic analysis of these 27,869 publications was performed using topological and metric approaches.

Results

Results. As a result of systematic analysis at least 123 molecules were identified, that, in one way or another, modulate NO biosynthesis in the body. Molecules that improve NO metabolism can be conditionally divided into four groups: (1) macro- and micronutrients; (2) components of natural extracts; (3) medicines; (4) molecules that affect nitric oxide metabolism through the reparation of glycocalyx damage. Of the above variety of molecules that affect endothelium and NO biosynthesis, sulodexide stands out (by its effect on the endothelium and glycocalyx).

Conclusion

Conclusion. The use of sulodexide (a mixture of glycosaminoglycans with a high degree of pharmaceutical standardization) is one of the promising areas of therapy for endothelial dysfunction through the regeneration of glycocalyx, which is accompanied by the restoration of NO biosynthesis.

Актуальность

Актуальность. Монооксид азота (NO) – сигнальная молекула, которая играет важную роль во множестве физиологических процессов, включая регуляцию сосудистого тонуса, нейротрансмиссию, иммунитет, митохондриальное дыхание и сократительную функцию скелетных мышц. Определенные молекулы, являющиеся микронутриентами или действующими началами ряда лекарств, способствуют улучшению биосинтеза и секреции NO.

Цель

Цель: систематизация информации о влиянии различных молекул на модуляцию уровней NO в норме и при патологии.

Материал и методы

Материал и методы. Изучен массив из всех имеющихся к настоящему времени публикаций по фундаментальным и клиническим исследованиям влияния различных молекул на уровни NO. По запросу “nitric oxide” в базе биомедицинских публикаций PubMed/MEDLINE найдено 198 480 статей, а по запросу “nitric oxide AND endothelium” – 27 869 статей (с пиком количества публикаций в 2005 г.). После загрузки данной выборки проведен систематический анализ этих 27 869 публикаций с использованием топологического и метрического подходов.

Результаты

Результаты. По результатам систематического анализа выявлены по крайней мере 123 молекулы, которые так или иначе модулируют биосинтез NO в организме. Молекулы, улучшающие обмен NO, могут быть условно подразделены на четыре группы: 1) макрои микронутриенты; 2) компоненты природных экстрактов; 3) лекарственные препараты; 4) молекулы, воздействующие на обмен NO через репарацию повреждений гликокаликса. Из приведенного разнообразия молекул, оказывающих эффект на эндотелий и биосинтез NO, выделяется сулодексид (по воздействию на эндотелий и гликокаликс).

Заключение

Заключение. Применение сулодексида (смеси гликозаминогликанов с высокой степенью фармацевтической стандартизации) – одно из перспективных направлений терапии эндотелиальной дисфункции через регенерацию гликокаликса, что сопровождается восстановлением биосинтеза NO.

оксид азотадействующие начала лекарствэндотелиопатиягликозаминогликанытопологический анализ данныхсулодексидnitric oxideactive drug principlesendotheliopathyglycosaminoglycanstopological data analysissulodexideАвторы заявляют об отсутствии финансовой поддержкиThe authors declare no fundingReferencesЧучалин А.Г. Роль оксида азота в современной клинической практике: научный доклад на V Всероссийском конгрессе «Легочная гипертензия» (13 декабря 2017 г.). Пульмонология. 2018; 28 (4): 503–11. https://doi.org/10.18093/0869-0189-2018-28-4-503-511.Chuchalin A.G. A role of nitric oxide for the modern clinical practice: a scientific report at the 5th Pan-Russian Congress on pulmonary hypertension, December 13, 2017. Pulmonologiya. 2018; 28 (4): 503– 11 (in Russ.). https://doi.org/10.18093/0869-0189-2018-28-4-503-511.Cyr A.R., Huckaby L.V., Shiva S.S., Zuckerbraun B.S. Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020; 36 (2): 307–21. https://doi.org/10.1016/j.ccc.2019.12.009.Cyr A.R., Huckaby L.V., Shiva S.S., Zuckerbraun B.S. Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020; 36 (2): 307–21. https://doi.org/10.1016/j.ccc.2019.12.009.Clancy R.M., Amin A.R., Abramson S.B. The role of nitric oxide in inflammation and immunity. Arthritis Rheum. 1998; 41 (7): 1141–51. https://doi.org/10.1002/1529-0131(199807)41:73.0.CO;2-S.Clancy R.M., Amin A.R., Abramson S.B. The role of nitric oxide in inflammation and immunity. Arthritis Rheum. 1998; 41 (7): 1141–51. https://doi.org/10.1002/1529-0131(199807)41:73.0.CO;2-S.Торшин И.Ю., Громова О.А., Чучалин А.Г., Майорова Л.А. Витамины и другие нутриенты, поддерживающие гомеостаз оксида азота и противодействующие формированию эндотелиопатии. Неврология, нейропсихиатрия, психосоматика. 2024; 16 (6): 89–96. https://doi.org/10.14412/2074-2711-2024-6-89-96.Torshin I.Y., Gromova O.A., Chuchalin A.G., Mayorova L.A. Vitamins and other nutrients that support nitric oxide homeostasis and counteract the development of endotheliopathy. Nevrologiya, neiropsikhiatriya, psikhosomatika / Neurology, Neuropsychiatry, Psychosomatics. 2024; 16 (6): 89–96 (in Russ.). https://doi.org/10.14412/2074-2711-2024-6- 89-96.Prasad A., Andrews N.P., Padder F.A., et al. Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability. J Am Coll Cardiol. 1999; 34 (2): 507–14. https://doi.org/10.1016/s0735-1097(99)00216-8.Prasad A., Andrews N.P., Padder F.A., et al. Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability. J Am Coll Cardiol. 1999; 34 (2): 507–14. https://doi.org/10.1016/s0735-1097(99)00216-8.Lynch F.M., Austin C., Heagerty A.M., Izzard A.S. Adenosine and hypoxic dilation of rat coronary small arteries: roles of the ATP-sensitive potassium channel, endothelium, and nitric oxide. Am J Physiol Heart Circ Physiol. 2006; 290 (3): H1145–50. https://doi.org/10.1152/ajpheart.00314.2005.Lynch F.M., Austin C., Heagerty A.M., Izzard A.S. Adenosine and hypoxic dilation of rat coronary small arteries: roles of the ATP-sensitive potassium channel, endothelium, and nitric oxide. Am J Physiol Heart Circ Physiol. 2006; 290 (3): H1145–50. https://doi.org/10.1152/ajpheart.00314.2005.Sousa T., Fernandes E., Nunes C., et al. Scavenging of nitric oxide by an antagonist of adenosine receptors. J Pharm Pharmacol. 2005; 57 (3): 399–404. https://doi.org/10.1211/0022357055614.Sousa T., Fernandes E., Nunes C., et al. Scavenging of nitric oxide by an antagonist of adenosine receptors. J Pharm Pharmacol. 2005; 57 (3): 399–404. https://doi.org/10.1211/0022357055614.Sobrevia L., Yudilevich D.L., Mann G.E. Activation of A2-purinoceptors by adenosine stimulates L-arginine transport (system y+) and nitric oxide synthesis in human fetal endothelial cells. J Physiol. 1997; 499 (Pt 1): 135–40. https://doi.org/10.1113/jphysiol.1997.sp021916.Sobrevia L., Yudilevich D.L., Mann G.E. Activation of A2-purinoceptors by adenosine stimulates L-arginine transport (system y+) and nitric oxide synthesis in human fetal endothelial cells. J Physiol. 1997; 499 (Pt 1): 135–40. https://doi.org/10.1113/jphysiol.1997.sp021916.Ellwood A.J., Curtis M.J. Mechanism of 5-hydroxytryptamineinduced coronary vasodilation assessed by direct detection of nitric oxide production in guinea-pig isolated heart. Br J Pharmacol. 1996; 119 (4): 721–9. https://doi.org/10.1111/j.1476-5381.1996.tb15732.x.Ellwood A.J., Curtis M.J. Mechanism of 5-hydroxytryptamineinduced coronary vasodilation assessed by direct detection of nitric oxide production in guinea-pig isolated heart. Br J Pharmacol. 1996; 119 (4): 721–9. https://doi.org/10.1111/j.1476-5381.1996.tb15732.x.Federici M., Menghini R., Mauriello A., et al. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation. 2002; 106 (4): 466–72. https://doi.org/10.1161/01.cir.0000023043.02648.51.Federici M., Menghini R., Mauriello A., et al. Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells. Circulation. 2002; 106 (4): 466–72. https://doi.org/10.1161/01.cir.0000023043.02648.51.Schlichting D., McCollam J.S. Recognizing and managing severe sepsis: a common and deadly threat. South Med J. 2007; 100 (6): 594–600. https://doi.org/10.1097/SMJ.0b013e31804aa29f.Schlichting D., McCollam J.S. Recognizing and managing severe sepsis: a common and deadly threat. South Med J. 2007; 100 (6): 594–600. https://doi.org/10.1097/SMJ.0b013e31804aa29f.Torshin I.Y. On solvability, regularity, and locality of the problem of genome annotation. Pattern Recognit Image Anal. 2010; 20: 386–95. https://doi.org/10.1134/S1054661810030156.Torshin I.Y. On solvability, regularity, and locality of the problem of genome annotation. Pattern Recognit Image Anal. 2010; 20: 386–95. https://doi.org/10.1134/S1054661810030156.Громова О.А., Торшин И.Ю., Кобалава Ж.Д. и др. Дефицит магния и гиперкоагуляционные состояния: метрический анализ данных выборки пациентов 18–50 лет лечебно-профилактических учреждений России. Кардиология. 2018; 58 (4): 22–35. https://doi.org/10.18087/cardio.2018.4.10106.Gromova O.A., Torshin I.Yu., Kobalava Zh.D., et al. Deficit of magnesium and states of hypercoagulation: intellectual analysis of data obtained from a sample of patients aged 18–50 years from medical and preventive facilities in Russia. Kardiologiia. 2018; 58 (4): 22–35 (in Russ.). https://doi.org/10.18087/cardio.2018.4.10106.Торшин И.Ю., Громова О.А., Стаховская Л.В. и др. Анализ 19,9 млн публикаций базы данных PubMed/MEDLINE методами искусственного интеллекта: подходы к обобщению накопленных данных и феномен “fake news”. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2020; 13 (2): 146–63. https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.021.Torshin I.Yu., Gromova O.A., Stakhovskaya L.V., et al. Analysis of 19.9 million publications from the PubMed/MEDLINE database using artificial intelligence methods: approaches to the generalizations of accumulated data and the phenomenon of “fake news. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya / FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2020; 13 (2): 146–63 (in Russ.). https://doi.org/10.17749/2070-4909/farmakoekonomika.2020.021.Торшин И.Ю. О задачах оптимизации, возникающих при применении топологического анализа данных к поиску алгоритмов прогнозирования с фиксированными корректорами. Информатика и ее применения. 2023; 17 (2): 2–10. https://doi.org/10.14357/19922264230201.Torshin I.Yu. On optimization problems arising fromthe application of topological data analysis to the search for forecasting algorithms with fixed correctors. Informatics and Applications. 2023; 17 (2): 2–10 (in Russ.). https://doi.org/10.14357/19922264230201.Торшин И.Ю. О формировании множеств прецедентов на основе таблиц разнородных признаковых описаний методами топологической теории анализа данных. Информатика и ее применения. 2023; 17 (3): 2–7. https://doi.org/10.14357/19922264230301.Torshin I.Yu. On the formation of sets of precedents basedon tables of heterogeneous feature descriptions by methods of topological theory of data analysis. Informatics and Applications. 2023; 17 (3): 2–7 (in Russ.). https://doi.org/10.14357/19922264230301.Palmer R.M., Rees D.D., Ashton D.S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endotheliumdependent relaxation. Biochem Biophys Res Commun. 1988; 153 (3): 1251–6. https://doi.org/10.1016/s0006-291x(88)81362-7.Palmer R.M., Rees D.D., Ashton D.S., Moncada S. L-arginine is the physiological precursor for the formation of nitric oxide in endotheliumdependent relaxation. Biochem Biophys Res Commun. 1988; 153 (3): 1251–6. https://doi.org/10.1016/s0006-291x(88)81362-7.Jabłecka A., Bogdański P., Balcer N., et al. The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities. Eur Rev Med Pharmacol Sci. 2012; 16 (3): 342–50.Jabłecka A., Bogdański P., Balcer N., et al. The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities. Eur Rev Med Pharmacol Sci. 2012; 16 (3): 342–50.Morrissey J.J., Klahr S. Agmatine activation of nitric oxide synthase in endothelial cells. Proc Assoc Am Physicians. 1997; 109 (1): 51–7.Morrissey J.J., Klahr S. Agmatine activation of nitric oxide synthase in endothelial cells. Proc Assoc Am Physicians. 1997; 109 (1): 51–7.Adejare A., Oloyo A., Anigbogu C., Jaja S. L-arginine supplementation increased only endothelium-dependent relaxation in spraguedawley rats fed a high-salt diet by enhancing abdominal aorta endothelial nitric oxide synthase gene expression. Clin Med Insights Cardiol. 2020; 14: 1179546820902843. https://doi.org/10.1177/1179546820902843.Adejare A., Oloyo A., Anigbogu C., Jaja S. L-arginine supplementation increased only endothelium-dependent relaxation in spraguedawley rats fed a high-salt diet by enhancing abdominal aorta endothelial nitric oxide synthase gene expression. Clin Med Insights Cardiol. 2020; 14: 1179546820902843. https://doi.org/10.1177/1179546820902843.Nurkiewicz T.R., Wu G., Li P., Boegehold M.A. Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. Microcirculation. 2010; 17 (2): 147–57. https://doi.org/10.1111/j.1549-8719.2009.00014.x.Nurkiewicz T.R., Wu G., Li P., Boegehold M.A. Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. Microcirculation. 2010; 17 (2): 147–57. https://doi.org/10.1111/j.1549-8719.2009.00014.x.Heriansyah T., Dimiati H., Hadi T.F., et al. Ascorbic acid vs calcitriol in influencing monocyte chemoattractant protein-1, nitric oxide, superoxide dismutase, as markers of endothelial dysfunction: in vivo study in atherosclerosis rat model. Vasc Health Risk Manag. 2023; 19: 139–144. https://doi.org/10.2147/VHRM.S401521.Heriansyah T., Dimiati H., Hadi T.F., et al. Ascorbic acid vs calcitriol in influencing monocyte chemoattractant protein-1, nitric oxide, superoxide dismutase, as markers of endothelial dysfunction: in vivo study in atherosclerosis rat model. Vasc Health Risk Manag. 2023; 19: 139–144. https://doi.org/10.2147/VHRM.S401521.Trinity J.D., Wray D.W., Witman M.A., et al. Ascorbic acid improves brachial artery vasodilation during progressive handgrip exercise in the elderly through a nitric oxide-mediated mechanism. Am J Physiol Heart Circ Physiol. 2016; 310 (6): H765–74. https://doi.org/10.1152/ajpheart.00817.2015.Trinity J.D., Wray D.W., Witman M.A., et al. Ascorbic acid improves brachial artery vasodilation during progressive handgrip exercise in the elderly through a nitric oxide-mediated mechanism. Am J Physiol Heart Circ Physiol. 2016; 310 (6): H765–74. https://doi.org/10.1152/ajpheart.00817.2015.Wu J.R., Kao L.P., Wu B.N., et al. Buffered l-ascorbic acid, alone or bound to KMUP-1 or sildenafil, reduces vascular endothelium growth factor and restores endothelium nitric oxide synthase in hypoxic pulmonary artery. Kaohsiung J Med Sci. 2015; 31 (5): 241–54. https://doi.org/10.1016/j.kjms.2015.02.005.Wu J.R., Kao L.P., Wu B.N., et al. Buffered l-ascorbic acid, alone or bound to KMUP-1 or sildenafil, reduces vascular endothelium growth factor and restores endothelium nitric oxide synthase in hypoxic pulmonary artery. Kaohsiung J Med Sci. 2015; 31 (5): 241–54. https:// doi.org/10.1016/j.kjms.2015.02.005.Huang A., Vita J.A., Venema R.C., Keaney J.F. Jr. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000; 275 (23): 17399–406. https://doi.org/10.1074/jbc.M002248200.Huang A., Vita J.A., Venema R.C., Keaney J.F. Jr. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000; 275 (23): 17399– 406. https://doi.org/10.1074/jbc.M002248200.Stanhewicz A.E., Kenney W.L. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev. 2017; 75 (1): 61–70. https://doi.org/10.1093/nutrit/nuw053.Stanhewicz A.E., Kenney W.L. Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev. 2017; 75 (1): 61–70. https://doi.org/10.1093/nutrit/nuw053.Antoniades C., Shirodaria C., Warrick N., et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006; 114 (11): 1193–201. https://doi.org/10.1161/CIRCULATIONAHA.106.612325.Antoniades C., Shirodaria C., Warrick N., et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006; 114 (11): 1193–201. https://doi.org/10.1161/CIRCULATIONAHA.106.612325.Artunc F., Essig M., Artunc N., et al. Effects of tetrahydrobiopterin on nitric oxide bioavailability and renal hemodynamics in healthy volunteers. J Nephrol. 2008; 21 (6): 850–60.Artunc F., Essig M., Artunc N., et al. Effects of tetrahydrobiopterin on nitric oxide bioavailability and renal hemodynamics in healthy volunteers. J Nephrol. 2008; 21 (6): 850–60.Heller R., Werner-Felmayer G., Werner E.R. Alpha-tocopherol and endothelial nitric oxide synthesis. Ann NY Acad Sci. 2004; 1031: 74–85. https://doi.org/10.1196/annals.1331.007.Heller R., Werner-Felmayer G., Werner E.R. Alpha-tocopherol and endothelial nitric oxide synthesis. Ann NY Acad Sci. 2004; 1031: 74–85. https://doi.org/10.1196/annals.1331.007.Omura M., Kobayashi S., Mizukami Y., et al. Eicosapentaenoic acid (EPA) induces Ca(2+)-independent activation and translocation of endothelial nitric oxide synthase and endothelium-dependent vasorelaxation. FEBS Lett. 2001; 487 (3): 361–6. https://doi.org/10.1016/s0014-5793(00)02351-6.Omura M., Kobayashi S., Mizukami Y., et al. Eicosapentaenoic acid (EPA) induces Ca(2+)-independent activation and translocation of endothelial nitric oxide synthase and endothelium-dependent vasorelaxation. FEBS Lett. 2001; 487 (3): 361–6. https://doi.org/10.1016/s0014-5793(00)02351-6.Zgheel F., Perrier S., Remila L., et al. EPA:DHA 6:1 is a superior omega-3 PUFAs formulation attenuating platelets-induced contractile responses in porcine coronary and human internal mammary artery by targeting the serotonin pathway via an increased endothelial formation of nitric oxide. Eur J Pharmacol. 2019; 853: 41–8. https://doi.org/10.1016/j.ejphar.2019.03.022.Zgheel F., Perrier S., Remila L., et al. EPA:DHA 6:1 is a superior omega-3 PUFAs formulation attenuating platelets-induced contractile responses in porcine coronary and human internal mammary artery by targeting the serotonin pathway via an increased endothelial formation of nitric oxide. Eur J Pharmacol. 2019; 853: 41–8. https://doi.org/10.1016/j.ejphar.2019.03.022.Heitzer T., Finckh B., Albers S., et al. Beneficial effects of alphalipoic acid and ascorbic acid on endothelium-dependent, nitric oxidemediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic Biol Med. 2001; 31 (1): 53–61. https://doi.org/10.1016/s0891-5849(01)00551-2.Heitzer T., Finckh B., Albers S., et al. Beneficial effects of alphalipoic acid and ascorbic acid on endothelium-dependent, nitric oxidemediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic Biol Med. 2001; 31 (1): 53–61. https://doi.org/10.1016/s0891-5849(01)00551-2.Kasten T.P., Settle S.L., Misko T.P., et al. Manganese potentiation of nitric oxide-mediated vascular relaxation. Eur J Pharmacol. 1994; 253 (1-2): 35–43. https://doi.org/10.1016/0014-2999(94)90754-4.Kasten T.P., Settle S.L., Misko T.P., et al. Manganese potentiation of nitric oxide-mediated vascular relaxation. Eur J Pharmacol. 1994; 253 (1-2): 35–43. https://doi.org/10.1016/0014-2999(94)90754-4.Gioda C.R., Capettini L.S., Cruz J.S., Lemos V.S. Thiamine deficiency leads to reduced nitric oxide production and vascular dysfunction in rats. Nutr Metab Cardiovasc Dis. 2014; 24 (2): 183–8. https://doi.org/10.1016/j.numecd.2013.06.010.Gioda C.R., Capettini L.S., Cruz J.S., Lemos V.S. Thiamine deficiency leads to reduced nitric oxide production and vascular dysfunction in rats. Nutr Metab Cardiovasc Dis. 2014; 24 (2): 183–8. https://doi.org/10.1016/j.numecd.2013.06.010.Wallerath T., Deckert G., Ternes T., et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002; 106 (13): 1652–8. https://doi.org/10.1161/01.cir.0000029925.18593.5c.Wallerath T., Deckert G., Ternes T., et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 2002; 106 (13): 1652–8. https://doi.org/10.1161/01.cir.0000029925.18593.5c.DiNatale J.C., Crowe-White K.M. Effects of resveratrol supplementation on nitric oxide-mediated vascular outcomes in hypertension: a systematic review. Nitric Oxide. 2022; 129: 74–81. https://doi.org/10.1016/j.niox.2022.10.005.DiNatale J.C., Crowe-White K.M. Effects of resveratrol supplementation on nitric oxide-mediated vascular outcomes in hypertension: a systematic review. Nitric Oxide. 2022; 129: 74–81. https://doi.org/10.1016/j.niox.2022.10.005.Xia N., Förstermann U., Li H. Resveratrol and endothelial nitric oxide. Molecules. 2014; 19 (10): 16102–21. https://doi.org/10.3390/molecules191016102.Xia N., Förstermann U., Li H. Resveratrol and endothelial nitric oxide. Molecules. 2014; 19 (10): 16102–21. https://doi.org/10.3390/molecules191016102.Wang N., Ko S.H., Chai W., et al. Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFα. Am J Physiol Endocrinol Metab. 2011; 300 (1): E195–201. https://doi.org/10.1152/ajpendo.00414.2010.Wang N., Ko S.H., Chai W., et al. Resveratrol recruits rat muscle microvasculature via a nitric oxide-dependent mechanism that is blocked by TNFα. Am J Physiol Endocrinol Metab. 2011; 300 (1): E195– 201. https://doi.org/10.1152/ajpendo.00414.2010.Santos-Parker J.R., Strahler T.R., Bassett C.J., et al. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging. 2017; 9 (1): 187–208. https://doi.org/10.18632/aging.101149.Santos-Parker J.R., Strahler T.R., Bassett C.J., et al. Curcumin supplementation improves vascular endothelial function in healthy middle-aged and older adults by increasing nitric oxide bioavailability and reducing oxidative stress. Aging. 2017; 9 (1): 187–208. https://doi.org/10.18632/aging.101149.Park S.H., Jeong S.O., Chung H.T., Pae H.O. Pterostilbene, an active constituent of blueberries, stimulates nitric oxide production via activation of endothelial nitric oxide synthase in human umbilical vein endothelial cells. Plant Foods Hum Nutr. 2015; 70 (3): 263–8. https://doi.org/10.1007/s11130-015-0488-3.Park S.H., Jeong S.O., Chung H.T., Pae H.O. Pterostilbene, an active constituent of blueberries, stimulates nitric oxide production via activation of endothelial nitric oxide synthase in human umbilical vein endothelial cells. Plant Foods Hum Nutr. 2015; 70 (3): 263–8. https://doi.org/10.1007/s11130-015-0488-3.Lorenz M., Wessler S., Follmann E., et al. A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. J Biol Chem. 2004; 279 (7): 6190–5. https://doi.org/10.1074/jbc.M309114200.Lorenz M., Wessler S., Follmann E., et al. A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a phosphatidylinositol-3-OH-kinase-, cAMP-dependent protein kinase-, and Akt-dependent pathway and leads to endothelial-dependent vasorelaxation. J Biol Chem. 2004; 279 (7): 6190–5. https://doi.org/10.1074/jbc.M309114200.Hien T.T., Kim N.D., Pokharel Y.R., et al. Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptordependent PI3-kinase and AMP-activated protein kinase. Toxicol Appl Pharmacol. 2010; 246 (3): 171–83. https://doi.org/10.1016/j.taap.2010.05.008.Hien T.T., Kim N.D., Pokharel Y.R., et al. Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptordependent PI3-kinase and AMP-activated protein kinase. Toxicol Appl Pharmacol. 2010; 246 (3): 171–83. https://doi.org/10.1016/j.taap. 2010.05.008.Duarte J., Francisco V., Perez-Vizcaino F. Modulation of nitric oxide by flavonoids. Food Funct. 2014; 5 (8): 1653–68. https://doi.org/10.1039/c4fo00144c.Duarte J., Francisco V., Perez-Vizcaino F. Modulation of nitric oxide by flavonoids. Food Funct. 2014; 5 (8): 1653–68. https://doi.org/10.1039/c4fo00144c.Machha A., Achike F.I., Mustafa A.M., Mustafa M.R. Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide. 2007; 16 (4): 442–7. https://doi.org/10.1016/j.niox.2007.04.001.Machha A., Achike F.I., Mustafa A.M., Mustafa M.R. Quercetin, a flavonoid antioxidant, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide. 2007; 16 (4): 442–7. https://doi.org/10.1016/j.niox.2007.04.001.Bai J., Wang Q., Qi J., et al. Promoting effect of baicalin on nitric oxide production in CMECs via activating the PI3K-AKT-eNOS pathway attenuates myocardial ischemia-reperfusion injury. Phytomedicine. 2019; 63: 153035. https://doi.org/10.1016/j.phymed.2019.153035.Bai J., Wang Q., Qi J., et al. Promoting effect of baicalin on nitric oxide production in CMECs via activating the PI3K-AKT-eNOS pathway attenuates myocardial ischemia-reperfusion injury. Phytomedicine. 2019; 63: 153035. https://doi.org/10.1016/j.phymed.2019.153035.Villar I.C., Vera R., Galisteo M., et al. Endothelial nitric oxide production stimulated by the bioflavonoid chrysin in rat isolated aorta. Planta Med. 2005; 71 (9): 829–34. https://doi.org/10.1055/s-2005-871296.Villar I.C., Vera R., Galisteo M., et al. Endothelial nitric oxide production stimulated by the bioflavonoid chrysin in rat isolated aorta. Planta Med. 2005; 71 (9): 829–34. https://doi.org/10.1055/s-2005-871296.Koizumi H., Yu J., Hashimoto R., et al. Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. FEBS Lett. 2010; 584 (11): 2440–4. https://doi.org/10.1016/j.febslet.2010.04.049.Koizumi H., Yu J., Hashimoto R., et al. Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. FEBS Lett. 2010; 584 (11): 2440–4. https://doi.org/10.1016/j.febslet.2010.04.049.Li R., Guo M., Zhang G., et al. Nicotiflorin reduces cerebral ischemic damage and upregulates endothelial nitric oxide synthase in primarily cultured rat cerebral blood vessel endothelial cells. J Ethnopharmacol. 2006; 107 (1): 143–50. https://doi.org/10.1016/j.jep.2006.04.024.Li R., Guo M., Zhang G., et al. Nicotiflorin reduces cerebral ischemic damage and upregulates endothelial nitric oxide synthase in primarily cultured rat cerebral blood vessel endothelial cells. J Ethnopharmacol. 2006; 107 (1): 143–50. https://doi.org/10.1016/j.jep.2006.04.024.Erdogan A., Most A.K., Wienecke B., et al. Apigenin-induced nitric oxide production involves calcium-activated potassium channels and is responsible for antiangiogenic effects. J Thromb Haemost. 2007; 5 (8): 1774–81. https://doi.org/10.1111/j.1538-7836.2007.02615.x.Erdogan A., Most A.K., Wienecke B., et al. Apigenin-induced nitric oxide production involves calcium-activated potassium channels and is responsible for antiangiogenic effects. J Thromb Haemost. 2007; 5 (8): 1774–81. https://doi.org/10.1111/j.1538-7836.2007.02615.x.Gwozdzinski L., Bernasinska-Slomczewska J., Hikisz P., et al. The effect of diosmin, escin, and bromelain on human endothelial cells derived from the umbilical vein and the varicose vein – a preliminary study. Biomedicines. 2023; 11 (6): 1702. https://doi.org/10.3390/biomedicines11061702.Gwozdzinski L., Bernasinska-Slomczewska J., Hikisz P., et al. The effect of diosmin, escin, and bromelain on human endothelial cells derived from the umbilical vein and the varicose vein – a preliminary study. Biomedicines. 2023; 11 (6): 1702. https://doi.org/10.3390/biomedicines11061702.de Almeida G.K.M., Jesus I.C.G., Mesquita T., et al. Post-ischemic reperfusion with diosmin attenuates myocardial injury through a nitric oxidase synthase-dependent mechanism. Life Sci. 2020; 258: 118188. https://doi.org/10.1016/j.lfs.2020.118188.de Almeida G.K.M., Jesus I.C.G., Mesquita T., et al. Post-ischemic reperfusion with diosmin attenuates myocardial injury through a nitric oxidase synthase-dependent mechanism. Life Sci. 2020; 258: 118188. https://doi.org/10.1016/j.lfs.2020.118188.Silambarasan T., Raja B. Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats. Eur J Pharmacol. 2012; 679 (1-3): 81–9. https://doi.org/10.1016/j.ejphar.2011.12.040.Silambarasan T., Raja B. Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats. Eur J Pharmacol. 2012; 679 (1-3): 81–9. https://doi.org/10.1016/j.ejphar.2011.12.040.Gao G., Nakamura S., Asaba S., et al. Hesperidin preferentially stimulates transient receptor potential vanilloid 1, leading to NO production and mas receptor expression in human umbilical vein endothelial cells. J Agric Food Chem. 2022; 70 (36): 11290–300. https://doi.org/10.1021/acs.jafc.2c04045.Gao G., Nakamura S., Asaba S., et al. Hesperidin preferentially stimulates transient receptor potential vanilloid 1, leading to NO production and mas receptor expression in human umbilical vein endothelial cells. J Agric Food Chem. 2022; 70 (36): 11290–300. https://doi.org/10.1021/acs.jafc.2c04045.Dobiaš L., Petrová M., Vojtko R., Kristová V. Long-term treatment with hesperidin improves endothelium-dependent vasodilation in femoral artery of spontaneously hypertensive rats: the involvement of NO-synthase and K(v) channels. Phytother Res. 2016; 30 (10): 1665–71. https://doi.org/10.1002/ptr.5670.Dobiaš L., Petrová M., Vojtko R., Kristová V. Long-term treatment with hesperidin improves endothelium-dependent vasodilation in femoral artery of spontaneously hypertensive rats: the involvement of NO-synthase and K(v) channels. Phytother Res. 2016; 30 (10): 1665– 71. https://doi.org/10.1002/ptr.5670.Gaur V., Aggarwal A., Kumar A. Possible nitric oxide mechanism in the protective effect of hesperidin against ischemic reperfusion cerebral injury in rats. Indian J Exp Biol. 2011; 49 (8): 609–18.Gaur V., Aggarwal A., Kumar A. Possible nitric oxide mechanism in the protective effect of hesperidin against ischemic reperfusion cerebral injury in rats. Indian J Exp Biol. 2011; 49 (8): 609–18.Gaur V., Kumar A. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep. 2010; 62 (4): 635–48. https://doi.org/10.1016/s1734-1140(10)70321-2.Gaur V., Kumar A. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep. 2010; 62 (4): 635–48. https://doi.org/10.1016/s1734-1140(10)70321-2.Donato F., de Gomes M.G., Goes A.T., et al. Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: possible role of l-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull. 2014; 104: 19–26. https://doi.org/10.1016/j.brainresbull.2014.03.004.Donato F., de Gomes M.G., Goes A.T., et al. Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: possible role of l-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull. 2014; 104: 19–26. https://doi.org/10.1016/j.brainresbull.2014.03.004.Kumar A., Lalitha S., Mishra J. Possible nitric oxide mechanism in the protective effect of hesperidin against pentylenetetrazole (PTZ)-induced kindling and associated cognitive dysfunction in mice. Epilepsy Behav. 2013; 29 (1): 103–11. https://doi.org/10.1016/j.yebeh.2013.06.007.Kumar A., Lalitha S., Mishra J. Possible nitric oxide mechanism in the protective effect of hesperidin against pentylenetetrazole (PTZ)-induced kindling and associated cognitive dysfunction in mice. Epilepsy Behav. 2013; 29 (1): 103–11. https://doi.org/10.1016/j.yebeh.2013.06.007.Rizza S., Muniyappa R., Iantorno M., et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011; 96 (5): E782–92. https://doi.org/10.1210/jc.2010-2879.Rizza S., Muniyappa R., Iantorno M., et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011; 96 (5): E782–92. https://doi.org/10.1210/jc.2010-2879.Xiao H.B., Jun-Fang, Lu X.Y., et al. Protective effects of kaempferol against endothelial damage by an improvement in nitric oxide production and a decrease in asymmetric dimethylarginine level. Eur J Pharmacol. 2009; 616 (1-3): 213–22. https://doi.org/10.1016/j.ejphar.2009.06.022.Xiao H.B., Jun-Fang, Lu X.Y., et al. Protective effects of kaempferol against endothelial damage by an improvement in nitric oxide production and a decrease in asymmetric dimethylarginine level. Eur J Pharmacol. 2009; 616 (1-3): 213–22. https://doi.org/10.1016/j.ejphar.2009.06.022.Steffen Y., Schewe T., Sies H. (-)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem Biophys Res Commun. 2007; 359 (3): 828–33. https://doi.org/10.1016/j.bbrc.2007.05.200.Steffen Y., Schewe T., Sies H. (-)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase. Biochem Biophys Res Commun. 2007; 359 (3): 828–33. https://doi.org/10.1016/j.bbrc.2007.05.200.Lee G.H., Hoang T.H., Jung E.S., et al. Anthocyanins attenuate endothelial dysfunction through regulation of uncoupling of nitric oxide synthase in aged rats. Aging Cell. 2020; 19 (12): e13279. https://doi.org/10.1111/acel.13279.Lee G.H., Hoang T.H., Jung E.S., et al. Anthocyanins attenuate endothelial dysfunction through regulation of uncoupling of nitric oxide synthase in aged rats. Aging Cell. 2020; 19 (12): e13279. https://doi.org/10.1111/acel.13279.Xu J.W., Ikeda K., Yamori Y. Upregulation of endothelial nitric oxide synthase by cyanidin-3-glucoside, a typical anthocyanin pigment. Hypertension. 2004; 44 (2): 217–22. https://doi.org/10.1161/01.HYP.0000135868.38343.c6.Xu J.W., Ikeda K., Yamori Y. Upregulation of endothelial nitric oxide synthase by cyanidin-3-glucoside, a typical anthocyanin pigment. Hypertension. 2004; 44 (2): 217–22. https://doi.org/10.1161/01.HYP.0000135868.38343.c6.Yang Y., Nie W., Yuan J., et al. Genistein activates endothelial nitric oxide synthase in broiler pulmonary arterial endothelial cells by an Akt-dependent mechanism. Exp Mol Med. 2010; 42 (11): 768–76. https://doi.org/10.3858/emm.2010.42.11.078.Yang Y., Nie W., Yuan J., et al. Genistein activates endothelial nitric oxide synthase in broiler pulmonary arterial endothelial cells by an Akt-dependent mechanism. Exp Mol Med. 2010; 42 (11): 768–76. https://doi.org/10.3858/emm.2010.42.11.078.Lin A.H., Leung G.P., Leung S.W., et al. Genistein enhances relaxation of the spontaneously hypertensive rat aorta by transactivation of epidermal growth factor receptor following binding to membrane estrogen receptors-α and activation of a G protein-coupled, endothelial nitric oxide synthase. Pharmacol Res. 2011; 63 (3): 181–9. https://doi.org/10.1016/j.phrs.2010.11.007.Lin A.H., Leung G.P., Leung S.W., et al. Genistein enhances relaxation of the spontaneously hypertensive rat aorta by transactivation of epidermal growth factor receptor following binding to membrane estrogen receptors-α and activation of a G protein-coupled, endothelial nitric oxide synthase. Pharmacol Res. 2011; 63 (3): 181–9. https://doi.org/10.1016/j.phrs.2010.11.007.Woodman O.L., Missen M.A., Boujaoude M. Daidzein and 17 betaestradiol enhance nitric oxide synthase activity associated with an increase in calmodulin and a decrease in caveolin-1. J Cardiovasc Pharmacol. 2004; 44 (2): 155–63. https://doi.org/10.1097/00005344-200408000-00003.Woodman O.L., Missen M.A., Boujaoude M. Daidzein and 17 betaestradiol enhance nitric oxide synthase activity associated with an increase in calmodulin and a decrease in caveolin-1. J Cardiovasc Pharmacol. 2004; 44 (2): 155–63. https://doi.org/10.1097/00005344-200408000-00003.Yan L.P., Chan S.W., Chan A.S., et al. Puerarin decreases serum total cholesterol and enhances thoracic aorta endothelial nitric oxide synthase expression in diet-induced hypercholesterolemic rats. Life Sci. 2006; 79 (4): 324–30. https://doi.org/10.1016/j.lfs.2006.01.016.Yan L.P., Chan S.W., Chan A.S., et al. Puerarin decreases serum total cholesterol and enhances thoracic aorta endothelial nitric oxide synthase expression in diet-induced hypercholesterolemic rats. Life Sci. 2006; 79 (4): 324–30. https://doi.org/10.1016/j.lfs.2006.01.016.Zhou Z., Zhou H., Zou X., et al. Formononetin regulates endothelial nitric oxide synthase to protect vascular endothelium in deep vein thrombosis rats. Int J Immunopathol Pharmacol. 2022; 36: 3946320221111117. https://doi.org/10.1177/03946320221111117.Zhou Z., Zhou H., Zou X., et al. Formononetin regulates endothelial nitric oxide synthase to protect vascular endothelium in deep vein thrombosis rats. Int J Immunopathol Pharmacol. 2022; 36: 3946320221111117. https://doi.org/10.1177/03946320221111117.Siamwala J.H., Dias P.M., Majumder S., et al. L-theanine promotes nitric oxide production in endothelial cells through eNOS phosphorylation. J Nutr Biochem. 2013; 24 (3): 595–605. https://doi.org/10.1016/j.jnutbio.2012.02.016.Siamwala J.H., Dias P.M., Majumder S., et al. L-theanine promotes nitric oxide production in endothelial cells through eNOS phosphorylation. J Nutr Biochem. 2013; 24 (3): 595–605. https://doi.org/10.1016/j.jnutbio.2012.02.016.Rodríguez C., González-Díez M., Badimon L., Martínez-González J. Sphingosine-1-phosphate: a bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb Haemost. 2009; 101 (4): 665–73.Rodríguez C., González-Díez M., Badimon L., Martínez-González J. Sphingosine-1-phosphate: a bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb Haemost. 2009; 101 (4): 665–73.Chen P.R., Tsai C.E., Chang H., et al. Sesamol induces nitric oxide release from human umbilical vein endothelial cells. Lipids. 2005; 40 (9): 955–61. https://doi.org/10.1007/s11745-005-1456-3.Chen P.R., Tsai C.E., Chang H., et al. Sesamol induces nitric oxide release from human umbilical vein endothelial cells. Lipids. 2005; 40 (9): 955–61. https://doi.org/10.1007/s11745-005-1456-3.Mitamura M., Horie S., Sakaguchi M., et al. Mesaconitine-induced relaxation in rat aorta: involvement of Ca2+ influx and nitric-oxide synthase in the endothelium. Eur J Pharmacol. 2002; 436 (3): 217–25. https://doi.org/10.1016/s0014-2999(01)01623-5.Mitamura M., Horie S., Sakaguchi M., et al. Mesaconitine-induced relaxation in rat aorta: involvement of Ca2+ influx and nitric-oxide synthase in the endothelium. Eur J Pharmacol. 2002; 436 (3): 217–25. https://doi.org/10.1016/s0014-2999(01)01623-5.Madajka M., Korda M., White J., Malinski T. Effect of aspirin on constitutive nitric oxide synthase and the biovailability of NO. Thromb Res. 2003; 110 (5–6): 317–21. https://doi.org/10.1016/s0049-3848(03)00419-5.Madajka M., Korda M., White J., Malinski T. Effect of aspirin on constitutive nitric oxide synthase and the biovailability of NO. Thromb Res. 2003; 110 (5–6): 317–21. https://doi.org/10.1016/s0049-3848(03)00419-5.Taubert D., Berkels R., Grosser N., et al. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol. 2004; 143 (1): 159–65. https://doi.org/10.1038/sj.bjp.0705907.Taubert D., Berkels R., Grosser N., et al. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol. 2004; 143 (1): 159–65. https://doi.org/10.1038/sj.bjp.0705907.Senbel A.M., AbdelMoneim L., Omar A.G. Celecoxib modulates nitric oxide and reactive oxygen species in kidney ischemia/reperfusion injury and rat aorta model of hypoxia/reoxygenation. Vascul Pharmacol. 2014; 62 (1): 24–31. https://doi.org/10.1016/j.vph.2014.04.004.Senbel A.M., AbdelMoneim L., Omar A.G. Celecoxib modulates nitric oxide and reactive oxygen species in kidney ischemia/reperfusion injury and rat aorta model of hypoxia/reoxygenation. Vascul Pharmacol. 2014; 62 (1): 24–31. https://doi.org/10.1016/j.vph.2014.04.004.Kalinowski L., Dobrucki L.W., Szczepanska-Konkel M., et al. Thirdgeneration beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003; 107 (21): 2747–52. https://doi.org/10.1161/01.CIR.0000066912.58385.DE.Kalinowski L., Dobrucki L.W., Szczepanska-Konkel M., et al. Thirdgeneration beta-blockers stimulate nitric oxide release from endothelial cells through ATP efflux: a novel mechanism for antihypertensive action. Circulation. 2003; 107 (21): 2747–52. https://doi.org/10.1161/01.CIR.0000066912.58385.DE.Ladage D., Brixius K., Hoyer H., et al. Mechanisms underlying nebivolol-induced endothelial nitric oxide synthase activation in human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol. 2006; 33 (8): 720–4. https://doi.org/10.1111/j.1440-1681.2006.04424.x.Ladage D., Brixius K., Hoyer H., et al. Mechanisms underlying nebivolol-induced endothelial nitric oxide synthase activation in human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol. 2006; 33 (8): 720–4. https://doi.org/10.1111/j.1440-1681.2006.04424.x.Priviero F.B., Teixeira C.E., Claudino M.A., et al. Vascular effects of long-term propranolol administration after chronic nitric oxide blockade. Eur J Pharmacol. 2007; 571 (2–3): 189–96. https://doi.org/10.1016/j.ejphar.2007.05.060.Priviero F.B., Teixeira C.E., Claudino M.A., et al. Vascular effects of long-term propranolol administration after chronic nitric oxide blockade. Eur J Pharmacol. 2007; 571 (2–3): 189–96. https://doi.org/10.1016/j.ejphar.2007.05.060.Sahach V.F., Baziliuk O.V., Stepanenko L.H., et al. Effect of enalapril on nitric oxide synthesis, oxidative metabolism, and vascular tone in aging rats. Fiziol Zh (1994). 2007; 53 (4): 15–26 (in Ukranian).Sahach V.F., Baziliuk O.V., Stepanenko L.H., et al. Effect of enalapril on nitric oxide synthesis, oxidative metabolism, and vascular tone in aging rats. Fiziol Zh (1994). 2007; 53 (4): 15–26 (in Ukranian).Gauthier K.M., Cepura C.J., Campbell W.B. ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries. Biol Chem. 2013; 394 (9): 1205–12. https://doi.org/10.1515/hsz-2012-0348.Gauthier K.M., Cepura C.J., Campbell W.B. ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries. Biol Chem. 2013; 394 (9): 1205–12. https://doi.org/10.1515/hsz-2012-0348.Imanishi T., Tsujioka H., Ikejima H., et al. Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension. 2008; 52 (3): 563–72. https://doi.org/10.1161/HYPERTENSIONAHA.108.111120.Imanishi T., Tsujioka H., Ikejima H., et al. Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension. 2008; 52 (3): 563–72. https://doi.org/10.1161/HYPERTENSIONAHA.108.111120.Ikejima H., Imanishi T., Tsujioka H., et al. Effects of telmisartan, a unique angiotensin receptor blocker with selective peroxisome proliferator-activated receptor-gamma-modulating activity, on nitric oxide bioavailability and atherosclerotic change. J Hypertens. 2008; 26 (5): 964–72. https://doi.org/10.1097/HJH.0b013e3282f52c36.Ikejima H., Imanishi T., Tsujioka H., et al. Effects of telmisartan, a unique angiotensin receptor blocker with selective peroxisome proliferator-activated receptor-gamma-modulating activity, on nitric oxide bioavailability and atherosclerotic change. J Hypertens. 2008; 26 (5): 964–72. https://doi.org/10.1097/HJH.0b013e3282f52c36.Wiemer G., Fink E., Linz W., et al. Furosemide enhances the release of endothelial kinins, nitric oxide and prostacyclin. J Pharmacol Exp Ther. 1994; 271 (3): 1611–5.Wiemer G., Fink E., Linz W., et al. Furosemide enhances the release of endothelial kinins, nitric oxide and prostacyclin. J Pharmacol Exp Ther. 1994; 271 (3): 1611–5.Seifert R. Rethinking pharmacological nomenclature. Trends Pharmacol Sci. 2018; 39 (9): 785–97. https://doi.org/10.1016/j.tips.2018.06.006.Seifert R. Rethinking pharmacological nomenclature. Trends Pharmacol Sci. 2018; 39 (9): 785–97. https://doi.org/10.1016/j.tips.2018.06.006.Torshin I.Yu. Physiology and medicine. Bioinformatics in the postgenomic era. Nova Science Pub Inc; 2007: 302 pp.Torshin I.Yu. Physiology and medicine. Bioinformatics in the postgenomic era. Nova Science Pub Inc; 2007: 302 pp.Berkels R., Egink G., Marsen T.A., et al. Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms. Hypertension. 2001; 37 (2): 240–5. https://doi.org/10.1161/01.hyp.37.2.240.Berkels R., Egink G., Marsen T.A., et al. Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms. Hypertension. 2001; 37 (2): 240–5. https://doi.org/10.1161/01.hyp.37.2.240.Yang J., Fukuo K., Morimoto S., et al. Pranidipine enhances the action of nitric oxide released from endothelial cells. Hypertension. 2000; 35 (1 Pt 1): 82–5. https://doi.org/10.1161/01.hyp.35.1.82.Yang J., Fukuo K., Morimoto S., et al. Pranidipine enhances the action of nitric oxide released from endothelial cells. Hypertension. 2000; 35 (1 Pt 1): 82–5. https://doi.org/10.1161/01.hyp.35.1.82.Berkels R., Taubert D., Bartels H., et al. Amlodipine increases endothelial nitric oxide by dual mechanisms. Pharmacology. 2004; 70 (1): 39–45. https://doi.org/10.1159/000074241.Berkels R., Taubert D., Bartels H., et al. Amlodipine increases endothelial nitric oxide by dual mechanisms. Pharmacology. 2004; 70 (1): 39–45. https://doi.org/10.1159/000074241.Matsubara M., Yao K., Hasegawa K. Benidipine, a dihydropyridinecalcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release. Pharmacol Res. 2006; 53 (1): 35–43. https://doi.org/10.1016/j.phrs.2005.08.006.Matsubara M., Yao K., Hasegawa K. Benidipine, a dihydropyridinecalcium channel blocker, inhibits lysophosphatidylcholine-induced endothelial injury via stimulation of nitric oxide release. Pharmacol Res. 2006; 53 (1): 35–43. https://doi.org/10.1016/j.phrs.2005.08.006.Dillon G.A., Stanhewicz A.E., Serviente C., et al. Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis. Microvasc Res. 2022; 144: 104421. https://doi.org/10.1016/j.mvr.2022.104421.Dillon G.A., Stanhewicz A.E., Serviente C., et al. Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis. Microvasc Res. 2022; 144: 104421. https://doi.org/10.1016/j.mvr.2022.104421.Jantzen F., Könemann S., Wolff B., et al. Isoprenoid depletion by statins antagonizes cytokine-induced down-regulation of endothelial nitric oxide expression and increases NO synthase activity in human umbilical vein endothelial cells. J Physiol Pharmacol. 2007; 58 (3): 503–14.Jantzen F., Könemann S., Wolff B., et al. Isoprenoid depletion by statins antagonizes cytokine-induced down-regulation of endothelial nitric oxide expression and increases NO synthase activity in human umbilical vein endothelial cells. J Physiol Pharmacol. 2007; 58 (3): 503–14.Skogastierna C., Luksha L., Kublickiene K., et al. Beneficial vasoactive endothelial effects of fluvastatin: focus on prostacyclin and nitric oxide. Heart Vessels. 2011; 26 (6): 628–36. https://doi.org/10.1007/s00380-010-0097-x.Skogastierna C., Luksha L., Kublickiene K., et al. Beneficial vasoactive endothelial effects of fluvastatin: focus on prostacyclin and nitric oxide. Heart Vessels. 2011; 26 (6): 628–36. https://doi.org/10.1007/s00380-010-0097-x.Suh J.W., Choi D.J., Chang H.J., et al. HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase. J Korean Med Sci. 2010; 25 (1): 16–23. https://doi.org/10.3346/jkms.2010.25.1.16.Suh J.W., Choi D.J., Chang H.J., et al. HMG-CoA reductase inhibitor improves endothelial dysfunction in spontaneous hypertensive rats via down-regulation of caveolin-1 and activation of endothelial nitric oxide synthase. J Korean Med Sci. 2010; 25 (1): 16–23. https://doi.org/10.3346/jkms.2010.25.1.16.Ott C., Schlaich M.P., Schmidt B.M., et al. Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia. Atherosclerosis. 2008; 196 (2): 704–11. https://doi.org/10.1016/j.atherosclerosis.2006.12.020.Ott C., Schlaich M.P., Schmidt B.M., et al. Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia. Atherosclerosis. 2008; 196 (2): 704–11. https://doi.org/10.1016/j.atherosclerosis.2006.12.020.Subramani J., Kathirvel K., Leo M.D., et al. Atorvastatin restores the impaired vascular endothelium-dependent relaxations mediated by nitric oxide and endothelium-derived hyperpolarizing factors but not hypotension in sepsis. J Cardiovasc Pharmacol. 2009; 54 (6): 526–34. https://doi.org/10.1097/FJC.0b013e3181bfafd6.Subramani J., Kathirvel K., Leo M.D., et al. Atorvastatin restores the impaired vascular endothelium-dependent relaxations mediated by nitric oxide and endothelium-derived hyperpolarizing factors but not hypotension in sepsis. J Cardiovasc Pharmacol. 2009; 54 (6): 526–34. https://doi.org/10.1097/FJC.0b013e3181bfafd6.Brandes R.P., Behra A., Lebherz C., et al. Lovastatin maintains nitric oxide – but not EDHF-mediated endothelium-dependent relaxation in the hypercholesterolemic rabbit carotid artery. Atherosclerosis. 1999; 142 (1): 97–104. https://doi.org/10.1016/s0021-9150(98)00197-x.Brandes R.P., Behra A., Lebherz C., et al. Lovastatin maintains nitric oxide – but not EDHF-mediated endothelium-dependent relaxation in the hypercholesterolemic rabbit carotid artery. Atherosclerosis. 1999; 142 (1): 97–104. https://doi.org/10.1016/s0021-9150(98)00197-x.O'Hora T.R., Markos F., Wiernsperger N.F., Noble M.I. Metformin causes nitric oxide-mediated dilatation in a shorter time than insulin in the iliac artery of the anesthetized pig. J Cardiovasc Pharmacol. 2012; 59 (2): 182–7. https://doi.org/10.1097/FJC.0b013e31823b4b94.O'Hora T.R., Markos F., Wiernsperger N.F., Noble M.I. Metformin causes nitric oxide-mediated dilatation in a shorter time than insulin in the iliac artery of the anesthetized pig. J Cardiovasc Pharmacol. 2012; 59 (2): 182–7. https://doi.org/10.1097/FJC.0b013e31823b4b94.Rajapakse N.W., Chong A.L., Zhang W.Z., Kaye D.M. Insulinmediated activation of the L-arginine nitric oxide pathway in man, and its impairment in diabetes. PLoS One. 2013; 8 (5): e61840. https://doi.org/10.1371/journal.pone.0061840.Rajapakse N.W., Chong A.L., Zhang W.Z., Kaye D.M. Insulinmediated activation of the L-arginine nitric oxide pathway in man, and its impairment in diabetes. PLoS One. 2013; 8 (5): e61840. https://doi.org/10.1371/journal.pone.0061840.Kim J., Oh Y.S., Shinn S.H. Troglitazone reverses the inhibition of nitric oxide production by high glucose in cultured bovine retinal pericytes. Exp Eye Res. 2005; 81 (1): 65–70. https://doi.org/10.1016/j.exer.2005.01.010.Kim J., Oh Y.S., Shinn S.H. Troglitazone reverses the inhibition of nitric oxide production by high glucose in cultured bovine retinal pericytes. Exp Eye Res. 2005; 81 (1): 65–70. https://doi.org/10.1016/j.exer.2005.01.010.Omae T., Nagaoka T., Tanano I., Yoshida A. Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, induces dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels. Invest Ophthalmol Vis Sci. 2011; 52 (9): 6749–56. https://doi.org/10.1167/iovs.10-6826.Omae T., Nagaoka T., Tanano I., Yoshida A. Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, induces dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels. Invest Ophthalmol Vis Sci. 2011; 52 (9): 6749–56. https://doi.org/10.1167/iovs.10-6826.Ueba H., Kuroki M., Hashimoto S., et al. Glimepiride induces nitric oxide production in human coronary artery endothelial cells via a PI3-kinase-Akt dependent pathway. Atherosclerosis. 2005; 183 (1): 35–9. https://doi.org/10.1016/j.atherosclerosis.2005.01.055.Ueba H., Kuroki M., Hashimoto S., et al. Glimepiride induces nitric oxide production in human coronary artery endothelial cells via a PI3- kinase-Akt dependent pathway. Atherosclerosis. 2005; 183 (1): 35–9. https://doi.org/10.1016/j.atherosclerosis.2005.01.055.Mason R.P., Jacob R.F., Kubant R., et al. Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats. J Cardiovasc Pharmacol. 2012; 60 (5): 467–73. https://doi.org/10.1097/FJC.0b013e31826be204.Mason R.P., Jacob R.F., Kubant R., et al. Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats. J Cardiovasc Pharmacol. 2012; 60 (5): 467–73. https://doi.org/10.1097/FJC.0b013e31826be204.Hafezi-Moghadam A., Simoncini T., Yang Z., et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med. 2002; 8 (5): 473–9. https://doi.org/10.1038/nm0502-473.Hafezi-Moghadam A., Simoncini T., Yang Z., et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med. 2002; 8 (5): 473–9. https://doi.org/10.1038/nm0502-473.Mutoh A., Isshiki M., Fujita T. Aldosterone enhances ligandstimulated nitric oxide production in endothelial cells. Hypertens Res. 2008; 31 (9): 1811–20. https://doi.org/10.1291/hypres.31.1811.Mutoh A., Isshiki M., Fujita T. Aldosterone enhances ligandstimulated nitric oxide production in endothelial cells. Hypertens Res. 2008; 31 (9): 1811–20. https://doi.org/10.1291/hypres.31.1811.Novella S., Laguna-Fernández A., Lázaro-Franco M., et al. Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDLtreated human arterial endothelial cells. Mol Cell Endocrinol. 2013; 365 (1): 11–6. https://doi.org/10.1016/j.mce.2012.08.020.Novella S., Laguna-Fernández A., Lázaro-Franco M., et al. Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDLtreated human arterial endothelial cells. Mol Cell Endocrinol. 2013; 365 (1): 11–6. https://doi.org/10.1016/j.mce.2012.08.020.Townsend E.A., Meuchel L.W., Thompson M.A., et al. Estrogen increases nitric-oxide production in human bronchial epithelium. J Pharmacol Exp Ther. 2011; 339 (3): 815–24. https://doi.org/10.1124/jpet.111.184416.Townsend E.A., Meuchel L.W., Thompson M.A., et al. Estrogen increases nitric-oxide production in human bronchial epithelium. J Pharmacol Exp Ther. 2011; 339 (3): 815–24. https://doi.org/10.1124/jpet.111.184416.Florian M., Lu Y., Angle M., Magder S. Estrogen induced changes in Akt-dependent activation of endothelial nitric oxide synthase and vasodilation. Steroids. 2004; 69 (10): 637–45. https://doi.org/10.1016/j.steroids.2004.05.016.Florian M., Lu Y., Angle M., Magder S. Estrogen induced changes in Akt-dependent activation of endothelial nitric oxide synthase and vasodilation. Steroids. 2004; 69 (10): 637–45. https://doi.org/10.1016/j.steroids.2004.05.016.Andozia M.B., Vieira C.S., Franceschini S.A., et al. Ethinylestradiol and estradiol have different effects on oxidative stress and nitric oxide synthesis in human endothelial cell cultures. Fertil Steril. 2010; 94 (5): 1578–82. https://doi.org/10.1016/j.fertnstert.2009.08.052.Andozia M.B., Vieira C.S., Franceschini S.A., et al. Ethinylestradiol and estradiol have different effects on oxidative stress and nitric oxide synthesis in human endothelial cell cultures. Fertil Steril. 2010; 94 (5): 1578–82. https://doi.org/10.1016/j.fertnstert.2009.08.052.Simoncini T., Fu X.D., Caruso A., et al. Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors. Hum Reprod. 2007; 22 (8): 2325–34. https://doi.org/10.1093/humrep/dem109.Simoncini T., Fu X.D., Caruso A., et al. Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors. Hum Reprod. 2007; 22 (8): 2325–34. https://doi.org/10.1093/humrep/dem109.Shalev M., Staerman F., Allain H., et al. Stimulation of P2y purinoceptors induces, via nitric oxide production, endotheliumdependent relaxation of human isolated corpus cavernosum. J Urol. 1999; 161 (3): 955–9.Shalev M., Staerman F., Allain H., et al. Stimulation of P2y purinoceptors induces, via nitric oxide production, endotheliumdependent relaxation of human isolated corpus cavernosum. J Urol. 1999; 161 (3): 955–9.Park K.E., Lee S., Bae S.I., et al T. Theophylline-induced endothelium-dependent vasodilation is mediated by increased nitric oxide release and phosphodiesterase inhibition in rat aorta. Gen Physiol Biophys. 2023; 42 (6): 469–78. https://doi.org/10.4149/gpb_2023023.Park K.E., Lee S., Bae S.I., et al T. Theophylline-induced endothelium-dependent vasodilation is mediated by increased nitric oxide release and phosphodiesterase inhibition in rat aorta. Gen Physiol Biophys. 2023; 42 (6): 469–78. https://doi.org/10.4149/gpb_2023023.Siman F.D., Silveira E.A., Fernandes A.A., et al. Ouabain induces nitric oxide release by a PI3K/Akt-dependent pathway in isolated aortic rings from rats with heart failure. J Cardiovasc Pharmacol. 2015; 65 (1): 28–38. https://doi.org/10.1097/FJC.0000000000000160.Siman F.D., Silveira E.A., Fernandes A.A., et al. Ouabain induces nitric oxide release by a PI3K/Akt-dependent pathway in isolated aortic rings from rats with heart failure. J Cardiovasc Pharmacol. 2015; 65 (1): 28–38. https://doi.org/10.1097/FJC.0000000000000160.Wang B., Luo T., Chen D., Ansley D.M. Propofol reduces apoptosis and up-regulates endothelial nitric oxide synthase protein expression in hydrogen peroxide-stimulated human umbilical vein endothelial cells. Anesth Analg. 2007; 105 (4): 1027–33. https://doi.org/10.1213/01.ane.0000281046.77228.91.Wang B., Luo T., Chen D., Ansley D.M. Propofol reduces apoptosis and up-regulates endothelial nitric oxide synthase protein expression in hydrogen peroxide-stimulated human umbilical vein endothelial cells. Anesth Analg. 2007; 105 (4): 1027–33. https://doi.org/10.1213/01.ane.0000281046.77228.91.Souza C.R.R., Caetano E.S.P., Rodrigues S.D., et al. Isoflurane increases the activity of the vascular matrix metalloproteinase-2 in nonpregnant rats and increases the nitric oxide metabolites in pregnancy. Biosci Rep. 2024; 44 (6): BSR20240192. https://doi.org/10.1042/BSR20240192.Souza C.R.R., Caetano E.S.P., Rodrigues S.D., et al. Isoflurane increases the activity of the vascular matrix metalloproteinase-2 in nonpregnant rats and increases the nitric oxide metabolites in pregnancy. Biosci Rep. 2024; 44 (6): BSR20240192. https://doi.org/10.1042/BSR20240192.Воронков А.В., Тюренков И.Н. Влияние сердечно-сосудистых средств на вазодилатирующую функцию эндотелия у животных с экспериментальной недостаточностью половых гормонов. Экспериментальная и клиническая фармакология. 2011; 74 (10): 23–5.Voronkov A.V., Tiurenkov I.N. Effect of cardiovascular drugs on vasodilating endothelial function in animals with experimental deficiency of sex hormones. Experimental and Clinical Pharmacology. 2011; 74 (10): 23–5 (in Russ.).Masola V., Zaza G., Onisto M., et al. Glycosaminoglycans, proteoglycans and sulodexide and the endothelium: biological roles and pharmacological effects. Int Angiol. 2014; 33 (3): 243–54.Masola V., Zaza G., Onisto M., et al. Glycosaminoglycans, proteoglycans and sulodexide and the endothelium: biological roles and pharmacological effects. Int Angiol. 2014; 33 (3): 243–54.Boels M.G.S., Koudijs A., Avramut M.C., et al. Systemic monocyte chemotactic protein-1 inhibition modifies renal macrophages and restores glomerular endothelial glycocalyx and barrier function in diabetic nephropathy. Am J Pathol. 2017; 187 (11): 2430–40. https://doi.org/10.1016/j.ajpath.2017.07.020.Boels M.G.S., Koudijs A., Avramut M.C., et al. Systemic monocyte chemotactic protein-1 inhibition modifies renal macrophages and restores glomerular endothelial glycocalyx and barrier function in diabetic nephropathy. Am J Pathol. 2017; 187 (11): 2430–40. https://doi.org/10.1016/j.ajpath.2017.07.020.Zhao F., Zhong L., Luo Y. Endothelial glycocalyx as an important factor in composition of blood-brain barrier. CNS Neurosci Ther. 2021; 27 (1): 26–35. https://doi.org/10.1111/cns.13560.Zhao F., Zhong L., Luo Y. Endothelial glycocalyx as an important factor in composition of blood-brain barrier. CNS Neurosci Ther. 2021; 27 (1): 26–35. https://doi.org/10.1111/cns.13560.Shen Y., He Y., Pan Y., et al. Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury. Front Pharmacol. 2024; 15: 1415145. https://doi.org/10.3389/fphar.2024.1415145.Shen Y., He Y., Pan Y., et al. Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury. Front Pharmacol. 2024; 15: 1415145. https://doi.org/10.3389/fphar.2024.1415145.Balistreri C.R., Monastero R. Neuroinflammation and neurodegenerative diseases: how much do we still not know? Brain Sci. 2023; 14 (1): 19. https://doi.org/10.3390/brainsci14010019.Balistreri C.R., Monastero R. Neuroinflammation and neurodegenerative diseases: how much do we still not know? Brain Sci. 2023; 14 (1): 19. https://doi.org/10.3390/brainsci14010019.Song J.W., Zullo J., Lipphardt M., et al. Endothelial glycocalyx-the battleground for complications of sepsis and kidney injury. Nephrol Dial Transplant. 2018; 33 (2): 203–11. https://doi.org/10.1093/ndt/gfx076.Song J.W., Zullo J., Lipphardt M., et al. Endothelial glycocalyx-the battleground for complications of sepsis and kidney injury. Nephrol Dial Transplant. 2018; 33 (2): 203–11. https://doi.org/10.1093/ndt/gfx076.Liu Y., Chen S., Liu S., et al. Association of endothelial glycocalyx shedding and coronary microcirculation assessed by an angiographyderived index of microcirculatory resistance in patients with suspected coronary artery disease. Front Cardiovasc Med. 2022; 9: 950102. https://doi.org/10.3389/fcvm.2022.950102.Liu Y., Chen S., Liu S., et al. Association of endothelial glycocalyx shedding and coronary microcirculation assessed by an angiographyderived index of microcirculatory resistance in patients with suspected coronary artery disease. Front Cardiovasc Med. 2022; 9: 950102. https://doi.org/10.3389/fcvm.2022.950102.Hána L., Kočí J., Pohnán R., et al. The significance of glycocalyx in surgery. Rozhl Chir. 2023; 102 (12): 453–8. https://doi.org/10.33699/PIS.2023.102.12.453-458.Hána L., Kočí J., Pohnán R., et al. The significance of glycocalyx in surgery. Rozhl Chir. 2023; 102 (12): 453–8. https://doi.org/10.33699/PIS.2023.102.12.453-458.Fei Y., Huang X., Ning F., et al. NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways. Biomed Pharmacother. 2024; 175: 116621. https://doi.org/10.1016/j.biopha.2024.116621.Fei Y., Huang X., Ning F., et al. NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways. Biomed Pharmacother. 2024; 175: 116621. https://doi.org/10.1016/j.biopha.2024.116621.Dörnyei G., Monos E., Kaley G., Koller A. Regular exercise enhances blood pressure lowering effect of acetylcholine by increased contribution of nitric oxide. Acta Physiol Hung. 2000; 87 (2): 127–38.Dörnyei G., Monos E., Kaley G., Koller A. Regular exercise enhances blood pressure lowering effect of acetylcholine by increased contribution of nitric oxide. Acta Physiol Hung. 2000; 87 (2): 127–38.Chen S.J., Wu C.C., Yen M.H. Exercise training activates largeconductance calcium-activated K(+) channels and enhances nitric oxide production in rat mesenteric artery and thoracic aorta. J Biomed Sci. 2001; 8 (3): 248–55. https://doi.org/10.1007/BF02256598.Chen S.J., Wu C.C., Yen M.H. Exercise training activates largeconductance calcium-activated K(+) channels and enhances nitric oxide production in rat mesenteric artery and thoracic aorta. J Biomed Sci. 2001; 8 (3): 248–55. https://doi.org/10.1007/BF02256598.Majerczak J., Grandys M., Duda K., et al. Moderate-intensity endurance training improves endothelial glycocalyx layer integrity in healthy young men. Exp Physiol. 2017; 102 (1): 70–85. https://doi.org/10.1113/EP085887.Majerczak J., Grandys M., Duda K., et al. Moderate-intensity endurance training improves endothelial glycocalyx layer integrity in healthy young men. Exp Physiol. 2017; 102 (1): 70–85. https://doi.org/10.1113/EP085887.Ors Yildirim N., Yildirim A.K., Demeli Ertus M., et al. Sulodexide inhibits arterial contraction via the endothelium-dependent nitric oxide pathway. J Clin Med. 2024; 13 (8): 2332. https://doi.org/10.3390/jcm13082332.Ors Yildirim N., Yildirim A.K., Demeli Ertus M., et al. Sulodexide inhibits arterial contraction via the endothelium-dependent nitric oxide pathway. J Clin Med. 2024; 13 (8): 2332. https://doi.org/10.3390/jcm13082332.Raffetto J.D., Calanni F., Mattana P, Khalil RA. Sulodexide promotes arterial relaxation via endothelium-dependent nitric oxide mediated pathway. Biochem Pharmacol. 2019; 166: 347–56. https://doi.org/10.1016/j.bcp.2019.04.021.Raffetto J.D., Calanni F., Mattana P, Khalil RA. Sulodexide promotes arterial relaxation via endothelium-dependent nitric oxide mediated pathway. Biochem Pharmacol. 2019; 166: 347–56. https://doi.org/10.1016/j.bcp.2019.04.021.Li T., Liu X., Zhao Z., et al. Sulodexide recovers endothelial function through reconstructing glycocalyx in the balloon-injury rat carotid artery model. Oncotarget. 2017; 8 (53): 91350–61. https://doi.org/10.18632/oncotarget.20518.Li T., Liu X., Zhao Z., et al. Sulodexide recovers endothelial function through reconstructing glycocalyx in the balloon-injury rat carotid artery model. Oncotarget. 2017; 8 (53): 91350–61. https://doi.org/10.18632/oncotarget.20518.Gabryel B., Jarząbek K., Machnik G., et al. Superoxide dismutase 1 and glutathione peroxidase 1 are involved in the protective effect of sulodexide on vascular endothelial cells exposed to oxygen-glucose deprivation. Microvasc Res. 2016; 103: 26–35. https://doi.org/10.1016/j.mvr.2015.10.001.Gabryel B., Jarząbek K., Machnik G., et al. Superoxide dismutase 1 and glutathione peroxidase 1 are involved in the protective effect of sulodexide on vascular endothelial cells exposed to oxygen-glucose deprivation. Microvasc Res. 2016; 103: 26–35. https://doi.org/10.1016/j.mvr.2015.10.001.Тюренков И.Н., Воронков А.В., Слиецанс А.А., Снигур Г.Л. Влияние мексидола и сулодексида на уровень специфических маркеров развития эндотелиальной дисфункции у животных с экспериментальным сахарным диабетом. Экспериментальная и клиническая фармакология. 2012; 75 (5): 14–6.Tiurenkov I.N., Voronkov A.V., Slietsans A.A., Snigur G.L. Effects of mexidol and sulodexide on the level of specific markers of endothelial dysfunction in animals with experimental diabetes mellitus. Experimental and Clinical Pharmacology. 2012; 75 (5): 14–6 (in Russ.).Li P., Ma L.L., Xie R.J., et al. Treatment of 5/6 nephrectomy rats with sulodexide: a novel therapy for chronic renal failure. Acta Pharmacol Sin. 2012; 33 (5): 644–51. https://doi.org/10.1038/aps.2012.2.Li P., Ma L.L., Xie R.J., et al. Treatment of 5/6 nephrectomy rats with sulodexide: a novel therapy for chronic renal failure. Acta Pharmacol Sin. 2012; 33 (5): 644–51. https://doi.org/10.1038/aps.2012.2.Broekhuizen L.N., Lemkes B.A., Mooij H.L., et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 2010; 53 (12): 2646–55. https://doi.org/10.1007/s00125-010-1910-x.Broekhuizen L.N., Lemkes B.A., Mooij H.L., et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 2010; 53 (12): 2646–55. https://doi.org/10.1007/s00125-010-1910-x.Olde Engberink R.H., Rorije N.M., Lambers Heerspink H.J., et al. The blood pressure lowering potential of sulodexide--a systematic review and meta-analysis. Br J Clin Pharmacol. 2015; 80 (6): 1245–53. https://doi.org/10.1111/bcp.12722.Olde Engberink R.H., Rorije N.M., Lambers Heerspink H.J., et al. The blood pressure lowering potential of sulodexide--a systematic review and meta-analysis. Br J Clin Pharmacol. 2015; 80 (6): 1245–53. https://doi.org/10.1111/bcp.12722.Charfeddine S., Ibnhadjamor H., Jdidi J., et al. Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-COVID-19: insights from TUNEndCOV study. Front Cardiovasc Med. 2022; 9: 866113. https://doi.org/10.3389/fcvm.2022.866113.Charfeddine S., Ibnhadjamor H., Jdidi J., et al. Sulodexide significantly improves endothelial dysfunction and alleviates chest pain and palpitations in patients with long-COVID-19: insights from TUNEndCOV study. Front Cardiovasc Med. 2022; 9: 866113. https://doi.org/10.3389/fcvm.2022.866113.Ćurko-Cofek B., Jenko M., TaleskaStupica G., et al. The crucial triad: endothelial glycocalyx, oxidative stress, and inflammation in cardiac surgery-exploring the molecular connections. Int J Mol Sci. 2024; 25 (20): 10891. https://doi.org/10.3390/ijms252010891.Ćurko-Cofek B., Jenko M., TaleskaStupica G., et al. The crucial triad: endothelial glycocalyx, oxidative stress, and inflammation in cardiac surgery-exploring the molecular connections. Int J Mol Sci. 2024; 25 (20): 10891. https://doi.org/10.3390/ijms252010891.Gaddi A.V., Capello F., Gheorghe-Fronea O., et al. Sulodexide improves pain-free walking distance in patients with lower extremity peripheral arterial disease: a systematic review and meta-analysis. JRSM Cardiovasc Dis. 2020; 9: 2048004020907002. https://doi.org/10.1177/2048004020907002.Gaddi A.V., Capello F., Gheorghe-Fronea O., et al. Sulodexide improves pain-free walking distance in patients with lower extremity peripheral arterial disease: a systematic review and meta-analysis. JRSM Cardiovasc Dis. 2020; 9: 2048004020907002. https://doi.org/10.1177/2048004020907002.Bignamini A.A., Matuška J. Sulodexide for the symptoms and signs of chronic venous disease: a systematic review and meta-analysis. Adv Ther. 2020; 37 (3): 1013–33. https://doi.org/10.1007/s12325-020-01232-1.Bignamini A.A., Matuška J. Sulodexide for the symptoms and signs of chronic venous disease: a systematic review and meta-analysis. Adv Ther. 2020; 37 (3): 1013–33. https://doi.org/10.1007/s12325-020-01232-1.

The authors declare that there are no conflicts of interest present.