EFFECTS OF MELATONIN ON BLOOD PRESSURE, ENDOTHELIAL FUNCTION AND VASCULAR STIFFNESS IN PATIENTS WITH METABOLIC SYNDROME AND SLEEP DISORDERS

Objective. To compare efficacy and safety of metformin monotherapy and metformin in combination with melatonin concerning the parameters of endothelial function and the vascular elasticity, arterial hypertension (HTN), vascular premature aging and sleep status in patients with metabolic syndrome (MS). Design and methods. We performed an open prospective, comparative, controlled, randomized trial in 3 parallel groups. Altogether 238 patients with MS (IDF, 2005), HTN 1–2 degrees (who reached target blood pressure (BP) with the current antihypertensive therapy) and sleep disorders (< 19 scores by the survey of subjective sleep characteristics) were randomized into 3 groups. All patients underwent a lifestyle modification, including changesin diet and physical activity, as well as the normalization of the “sleep-wakefulness” rhythm for 12 weeks. In addition, patients of the first group (n = 80) received monotherapy with metformin, patients of the second group (n = 78) received combined therapy with metformin and prolonged-release melatonin. The control group (n = 80) included patients who adhere to the lifestyle modification recommendations without any pharmacological intervention. The groups were comparable for baseline clinical and demographic characteristics. At baseline and after 12 weeks of therapy the endothelial function was evaluated by flow-dependent vasodilation. Also BP, vascular stiffness, anthropometric and metabolic parameters, adipocytokine status, vascular age, and sleep quality were assessed. Results. The results of the study confirmed the efficiency of the long-acting melatonin in combination with the standard therapy in patients with MS and circadian disorders. Melatonin normalizes the “sleep-wakefulness” rhythm. Moreover, it provides protective effect regarding endothelial function, has favorable profile of cardiovascular and metabolic effects, and slows vascular aging. No serious drug-related adverse events were registered during the follow-up. Conclusions. Melatonin supplementation to the traditional MS therapy in patients with sleep disorders is safe and effective regarding dissomnia, overweight, metabolic disorders, and also has additional benefits in terms of improvement of endothelial function, vascular stiffness, and daily BP profile.

1. Мычка В. Б., Блинова Н. В., Горностаев В. В., Сергиенко В. Б., Атауллаханова Д. М., Масенко В. П. и др. Медикаментозное лечение ожирения у больных метаболическим синдромом. Эффективная фармакотерапия. 2010;11:38–43. [Mychka VB, Blinova NV, Gornostaev VV, Sergienko VB, Ataullakhanova DM, Masenko VP et al. Pharmacological treatment of obesity in patients with metabolic syndrome. Effective Pharmacotherapy. 2010;11:38–43. In Russian].

2. Арушанян Э. Б., Мастягина О. А. Значение мелатонина для деятельности сердечно-сосудистой системы и ее фармакологической регуляции. Экспериментальная и клиническая фармакология. 2008;71(3):65–71. [Arushanyan EB, Mastyagina OA. The value of melatonin for the activity of the cardiovascular system and its pharmacological regulation. Experimental and Clinical Pharmacology. 2008;71(3):65–71. In Russian].

3. Мартынова А. Г., Кодочигова А. И., Киричук В. Ф., Ермолаев А. А. Артериальная гипертония и масса тела. Решенные и нерешенные проблемы. Клин. медицина. 2005;83(8):32–36. [Martynova AG, Kodochigova AI, Kirichuk VF, Ermolaev AA. Arterial hypertension and body weight. Solved and unsolved problems. Clinical Medicine. 2005;83(8):32–36. In Russian].

4. Шилов А. М., Авшалумов А. С., Синицина Е. Н., Марковский В. Б., Галанова А. С., Мацеевич С. А. Особенности лечения артериальной гипертонии у больных с метаболическим синдромом. Эффективная фармакотерапия. 2008;3:44–49. [Shilov AM, Avshalumov AS, Sinitsina EN, Markovsky VB, Galanova AS, Matseevich SA. Features of treatment of arterial hypertension in patients with metabolic syndrome. Efficient Pharmacotherapy. 2008;3:44–49. In Russian].

5. Pogan L, Bissonnette P, Parent L, Sauvé R. The effects of melatonin on Ca (2+) homeostasis in endothelial cells. J Pineal Res. 2002;33(1):37–47.

6. Dharmashankar K, Widlansky ME. Vascular endothelial function and hypertension: insights and directions. Curr Hypertens Rep. 2010;12(6):448–455.

7. Tunstall RR, Shukla P, Grazul-Bilska A, Sun C, O’Rourke ST. MT2 receptors mediate the inhibitory effects of melatonin on nitric oxide-induced relaxation of porcine isolated coronary arteries. J Pharmacol Exp Ther. 2011;336(1):127–133.

8. Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L. Beneficial effects of melatonin in cardiovascular disease. Annals of medicine. 2010;42(4):276–285.

9. Tengattini S, Reiter RJ, Tan DX, Terron MP, Rodella LF, Rezzani R. Cardiovascular diseases: protective effects of melatonin. Journal of Pineal Research. 2008;44 (1):16–25.

10. Pita ML, Hoyos M, Martin-Lacave I, Osuna C, Fernández-Santos JM, Guerrero JM. Long-term melatonin administration increases polyunsaturated fatty acid percentage in plasma lipids of hypercholesterolemic rats. Journal of pineal research. 2002;32(3):179–186.

11. Rodella LF, Rossini C, Favero G, Foglio E, Loreto C, Rezzani R. Nicotine-induced morphological changes in rat aorta: the protective role of melatonin. Cells Tissues Organs. 2012;195 (3):252–259.

12. Рапопорт С. И. Мелатонин: перспективы применения в клинике. М.: ИМА-ПРЕСС, 2014. 176 с. [Rapoport SI. Melatonin: prospects of application in the clinic. M.: IMA-PRESS, 2012. 176 p. In Russian].

13. Zimmet P, Alberti K, Serrano Ríos M. A New International Diabetes Federation (IDF) Worldwide Definition of the Metabolic Syndrome: the Rationale and the Results. Revista Española de Cardiología (English Edition). 2005;58(12):1371–1375.

14. Вейн А. М., Левин Я. И. «Инсомния». Клиническая медицина. 1998;8:52-56 [Wayne, AM, Ya. I. I. Levin. “Insomnia”. Clinical medicine. 1998;8:52-56. [In Russian].

15. Srijithesh PR, Shukla G, Srivastav A, Goyal V, Singh S, Behari M. Validity of the Berlin Questitijnnaire in identifying obstructive sleep apnea syndrome when administered to the informants of stroke patients. J Clin Neurosci. 2011;18(3):340–3.

16. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14(6):540–545.

17. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S et al. Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23(1):7–17.

18. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–370.

19. Akerstedt T, Nilsson PM. Sleep as restitution: an introduction. J Intern Med. 2003;254(1):6–12.

20. Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 2005;27(2): 131–135.

21. Korkmaz A, Topal T, Tan DX, Reiter RJ. Role of melatonin in metabolic regulation. Reviews in Endocrine and Metabolic Disorders. 2009;10(4):261–270.

22. Cardinali DP, Cano P, Jiménez-Ortega V, Esquifino AI. Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications. Neuroendocrinology. 2011;93(3): 133–142.

23. Laudon GE, Zisapel N. Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vasc Health Risk Manag. 2011;7:577–84.

24. Grossman E, Laudon M, Yalcin R, Zengil H, Peleg E, Sharabi Y et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. The Am J of Med. 2006;119(10):898– 902.

25. Cuende JI, Cuende N, Calaveras-Lagartos J. How to calculate vascular age with the SCORE project scales: a new method of cardiovascular risk evaluation. Eur Heart J. 2010;31(19): 2351–2358.