ENDOTHELIAL DYSFUNCTION IN ESSENTIAL HYPERTENSION IN ADOLESCENTS (CLINICAL AND EXPERIMENTAL STUDY)

Objective. The aim of the study was to evaluate endothelial dysfunction based on the blood concentration of endothelin 1 (ET‑1), nitric oxide (NO), serotonin (5‑HT) in essential hypertension (EHTN) in adolescents and in experimental animal models. Design and methods. The work was carried out in two stages. The clinical part was preceded by the investigation of experimental models of arterial hypertension (HTN). Twenty five immature male SHR rats aged 6–7 weeks and 10 immature male Wistar–Kyoto rats aged 6–7 weeks (control group) were examined. The clinical part of the study included 70 untreated male adolescents (mean age 15,63 ± 0,26 years), among them 24 people had a labile form of EHTN (LHTN), 30 had stable form of EHTN (SHTN), the control group included 16 subjects. All participants underwent 24-hour blood pressure monitoring. The plasma concentration of EN-1 (ET‑1) was determined by enzyme immunoassay, total concentration of stable metabolites of NO, 5‑HT in serum and platelets was measured. Results. The serum levels of ET-1 and 5-HT were higher in HTN groups than in the control group, and in adolescents with SHTN levels of both indices were higher compared to those with LHTN (p < 0,0001). Serotonin level in platelets in HTN groups was lower than in the control group (p < 0,0001). Compared to the control group, NO levels were higher in adolescents with LHTN, but lower in patients with SHTN (p < 0,0001). The changes in the level of ET‑1, 5‑HT and NO in plasma, serum and blood platelets in the experimental animal model were similar to those found in patients with labile and stable HTN. Conclusions. NO, ET‑1 and 5‑HT are early sensitive markers of endothelial dysfunction in EHTN in adolescent males, as well as in the experimental SHR rat model.

1. Леонтьева И. В. Проблема артериальной гипертензии у детей и подростков. Российский вестник перинатологии и педиатрии. 2006;51(5):7–18. [Leontieva IV. Arterial hypertension in children and adolescents. Rossiiskij Vestnik Perinatologii i Pediatrii = Russian Bulletin of Perinatology and Pediatrics. 2006;51(5):7–18. In Russian].

2. Александров М. Г., Бубнова А. А., Кисляк О. А. Профилактика сердечно-сосудистых заболеваний в детском и подростковом возрасте. Российские рекомендации. Российский кардиологический журнал. 2012;6S1(98):1–39. [Alexandrov MG, Bubnov AA, Kislyak OA. Prevention of cardiovascular diseases in childhood and adolescence. Russian recommendations. Rossiyskiy Kardiologicheskiy Zhurnal = Russian Journal of Cardiology. 2012;6S1(98):1–39. In Russian].

3. Anyaegbu EI, Dharni-Dharka VR. Hypertension in the teenager. Pediatr Clin North Am. 2014;61(1):131–151. doi:10.1016/ j.pcl.2013.09.011

4. Falkner B. Hypertension in children and adolescents: epidemiology and natral history. Pediatr Nephrol. 2010;25(7):1219– 1224. doi:10.1007/s00467–009–1200–3

5. Chiolero A, Madeleine G, Gabriel A, Burnier M, Paccaud F, Bovet P. Prevlence of elevated blood pressure and association with overweight in children of a rapidly developing country. J Hum Hypertens. 2007;21(2):120–127. doi:10.1038/sj.jhh.1002125

6. Рунихин А. Ю., Порядин Г. В., Савчук В. И. Молекулярные и клеточные механизмы патогенеза первичной артериальной гипертонии. Вестник РГМУ. 2011;6:5–10. [Runikhin AYu, Poryadin GV, Savchuk VI. Molecular and cellular mechanisms of the pathogenesis of primary hypertension. Bulletin of RSMU = Bulletin of Russian State Medical University. 2011;6:5–10. In Russian].

7. Куличенко М. П., Ушакова С. А., Петрушина А. Д., Кляшев С. М. Циркулирующие маркеры дисфункции эндотелия у подростков с артериальной гипертензией, ассоциированной с избытком массы тела и ожирением. Медицинская наука и образование Урала. 2015;16(1):15–19. [Kulichenko MP, Ushakova SA, Petrushina AD, Klyashev SM. Сirculating markers of endothelial dysfunction in adolescents with arterial hypertension associated with overweight and obesity. Meditsinskaya Nauka i Obrazovaniye Urala = Medical Science and Education of Ural. 2015;16(1):15–19. In Russian].

8. Machida T, Iizuka K, Hirafuji M. 5-hydroxytryptamine and its receptors in systemic vascular walls. Biological and Pharmaceutical Bulletin. 2013;36(9):1416–1419. http://doi.org/ 10.1248/bpb.b13–00344

9. Gamoh S, Hisa H, Yamamoto R. 5-hydroxytryptamine receptors as targets for drug therapies of vascular-related diseases. Biol Pharmaceut Bull. 2013;36 (9):1410–1415. http://doi.org/ 10.1248/bpb.b13–00317

10. Bhaskaran S, Zaluski J, Banes-Berceli A. Molecular interactions of serotonin (5-HT) and endothelin-1 in vascular smooth muscle cells: in vitro and ex vivo analyses. Am J Physiol Cell Physiol. 2014;306(2):43–51.doi:10.1152/ajpcell.00247.2013

11. Callebertt J, Esteve JM, Herve P, Peoc’h K, Tournois C, Drouet L et al. Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine (2B) receptors in mice. J Phar- macol Exp Ther. 2006;317(2):724–731. doi:https://doiorg/ 10.1124/jpet.105.098269

12. Маянская С. Д., Антонов А. Р., Попова А. А., Гребенкина И. А. Ранние маркеры дисфункции эндотелия в динамике развития артериальной гипертонии у лиц молодого возраста. Казанский медицинский журнал. 2009;90(1):32–37. [Mayanskaya SD, Antonov AR, Popova AA, Grebenkina IA. Early markers of endothelial dysfunction in the dynamics of development of arterial

13. hypertension in young people. Kazanskiy Meditsinskiy Zhurnal = Kazan Medical Journal. 2009;90(1):32–37. In Russian].

14. Akcaboy MM, Kula S, Göktas T, Nazlıel B, Terlemez S, Celik N et al. Effect of plasma NOx values on cardiac function in obese hypertensive and normotensive pediatric patients. Pediatr Nephrol. 2015;1:69–92. doi:10.1007/s00467–015–3223–2

15. Микашинович З. И., Нагорная Г. Ю., Коваленко Т. Д. Биохимические показатели повреждения эндотелия воспалительного генеза у подростков с артериальной гипертензией. Кубанский научный медицинский вестник. 2012;2:123– 125. [Mikashinowich ZI, Nagornaya GJ, KovalenkoT D. The biochemical markers of endothelial affection of inflammatory genesis at teenagers with arterial hypertension. Kubanskiy Nauchnyi Meditsinskiy Vestnik = Kuban Scientific Medical Bulletin. 2012;2:123–125. In Russian].

16. Gilinsky MA, Latysheva TV, Petrakova GM. Dimethylarginines and serotonin in the blood of spontaneously hypertensive rats. Bull Exp Biol Med 2009;148(6):849–51. https://www.ncbi. nlm.nih.gov/pubmed/21116488

17. Журавлев Д. А. Модели артериальной гипертензии. Спонтанно-гипертензивные крысы. Артериальная гипертензия. 2009;15(6):721–2. [Zhuravlyov DA. Hypertension models. Spontaneously hypertensive rats. Arterial’naya Gipertenziya = Arterial Hypertension. 2009;15(6):721–2. In Russian].

18. Махинько В. И., Никитин В. Н. Константы роста и функциональные периоды развития в постнатальной жизни белых крыс. Молекулярные и физиологические механизмы возрастного развития. Киев: Наукова Думка, 1975: 308–325. [Mahinko VI, Nikitin VN. Constant growth and functional development in periods of postnatal life of white rats. Molecular and physiological mechanisms of age-related development. Kiev: Naukova Dumka, 1975: 308–325. In Ukrainian].

19. Клинические рекомендации по детской кардиологии и ревматологии/под. ред. М. А. Школьниковой, Е. И. Алексеевой. Ассоциация детских кардиологов России. 2011: 503. [Clinical guidelines on pediatric cardiology and rheumatology. Ed. by Shkolnikova MA, Alexeyeva EI. Association of Children’s Cardiologists from Russia. 2011: 503. In Russian].

20. Nava E, Farré AL, Moreno C, Casado S, Moreau P, Cosentino F et al. Alterations to the nitric oxide pathway in the spontaneously hypertensive rat. J Hypertens. 1998;16(5):609–15. https://www.ncbi.nlm.nih.gov/pubmed/9797172

21. Манухина Е. Б., Малышев И. Ю. Роль оксида азота в развитии и предупреждении дисфункции эндотелия. Вестник ВГМУ. 2003;2(2):25–17. [Manukhina EB, Malyshev IYu. The role of nitric oxide in the development and prevention of endothelial dysfunction. Vestnik of VSMU. 2003;2(2):25–17. In Belarus].

22. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65(1):109–118. ISSN 1802–9973