Статья
Коморбидные инсомния и артериальная гипертензия: патогенетические модели и перспективные биомаркеры
В данной обзорной статье описаны основные механизмы возникновения и поддержания коморбидных инсомнии и артериальной гипертензии с учетом актуальных патогенетических сценариев инсомнии, включающих концепцию симпатической активации, нейробиологическую модель инсомнии и трехфакторную модель. Результаты единичных клинических исследований свидетельствуют о взаимосвязи уровней артериального давления с гиперактивацией центральной нервной системы во время сна, характеризуемой по электроэнцефалографической активности в диапазоне β-спектра, и с показателями латентности сна. Тем не менее биологически активные вещества, опосредующие так называемое «нейрогенное воспаление», также играют значимую роль в поддержании гомеостаза при воздействии эндогенных и экзогенных стрессорных факторов. Функции интерлейкина‑6, гамма-аминомасляной кислоты, субстанции Р, мелатонина, серотонина и орексина в норме и в патологии позволяют высказать предположение об их участии в механизмах реализации взаимосвязи инсомнии и артериальной гипертензии. Подчеркивается важность трактовки инсомнии в качестве отдельной нозологической единицы, сопутствующей артериальной гипертензии, и актуальность исследований молекулярных механизмов взаимосвязи инсомнии и артериальной гипертензии с целью определения перспективных терапевтических мишеней и прогностических маркеров при конкретном патогенетическом сценарии.
1. Zucconi M, Ferri R. Assessment of sleep disorders and diagnostic procedures. European Sleep Research Society. 2014.
2. Morin CM, Benca R. Chronic insomnia. The Lancet. 2012;379(9821):1129–41. doi:10.1016/S0140-6736(11)60750-2
3. Levenson JC, Kay DB, Buysse DJ. The pathophysiology of insomnia. Chest. 2015;147(4):1179–92. doi:10.1378/chest.14-1617
4. Buysse DJ. Insomnia. J Am Med Assoc 2012;309(7):706–16. doi:10.1001/jama.2013.193.Insomnia
5. Buysse DJ, Germain A, Hall M, Monk TH, Nofzinger EA. A neurobiological model of insomnia. Drug Discovery Today: Disease Models. 2011;8(4):129–137. doi:10.1016/j.ddmod.2011.07.002.A
6. Walsh JK, Coulouvrat C, Hajak G, Lakoma MD, Petukhova M, Roth T, et al. Nighttime insomnia symptoms and perceived health in the america insomnia survey (AIS). Sleep. 2011;34(8):997–1011. doi:10.5665/SLEEP.1150
7. Winkelman JW. Insomnia disorder. New England Journal of Medicine. 2015;373(15):1437–44. doi:10.1056/NEJMcp1412740
8. Javaheri S, Redline S. Insomnia and risk of cardiovascular disease. Chest. 2017;152(2):435–44. doi:10.1016/j.chest.2017.01.026
9. Jarrin DC, Alvaro PK, Bouchard MA, Jarrin SD, Drake CL, Morin CM. Insomnia and hypertension: A systematic review. Sleep Medicine Reviews. 2018;41:3–38. doi:10.1016/j.smrv.2018.02.003
10. Zhan Y, Chen R, Zhang F, Wang J, Sun Y, Ding R, et al. Insomnia and its association with hypertension in a communitybased population in China: A cross-sectional study. Heart Asia. 2014;6(1):88–93. doi:10.1136/heartasia‑2013-010440
11. Budhiraja R, Roth T, Hudgel DW, Budhiraja P, Drake CL. Prevalence and polysomnographic correlates of insomnia comorbid with medical disorders. Sleep. 2011;34(7):859–67. doi:10.5665/sleep.1114
12. Lin CL, Liu TC, Lin FH, Chung CH, Chien WC. Association between sleep disorders and hypertension in Taiwan: A nationwide population-based retrospective cohort study. J Hum Hypertens. 2016;31(3):220–4. doi:10.1038/jhh.2016.55
13. Bathgate CJ, Edinger JD, Wyatt JK, Krystal AD. Objective but not subjective short sleep duration associated with increased risk for hypertension in individuals with insomnia. Sleep. 2016;39(5): 1037–45. doi:10.5665/sleep.5748
14. Vgontzas AN, Liao D, Bixler EO, Chrousos GP, Vela-Bueno A. Insomnia with objective short sleep duration is associated with a high risk for hypertension. Sleep. 2009;32(4):491–7. doi:10.1093/sleep/32.4.491
15. Fernandez-Mendoza J, Vgontzas AN, Liao D, Shaffer ML, Vela-Bueno A, Basta M, et al. Insomnia with objective short sleep duration and incident hypertension: The Penn State Cohort. Hypertension. 2012;60(4):929–35. doi:10.1161/HYPERTENSIONAHA.112.193268
16. Ramos AR, Weng J, Wallace DM, Petrov MR, Wohlgemuth WK, Sotres-Alvarez D, et al. Sleep patterns and hypertension using actigraphy in the Hispanic Community Health Study/Study of Latinos. Chest. 2018;153(1):87–93. doi:10.1016/jchest.2017.09.028
17. Vozoris NT. Insomnia symptom frequency and hypertension risk. J Clin Psychiatry. 2014;75(06):616–23. doi:10.4088/jcp.13m08818
18. Uka MS, Oshida KY, Ugimori HS. Persistent insomnia is a predictor of hypertension in Japanese male workers. J Occup Health. 2003;45:344–50.
19. Phillips B, Bůžková P, Enright P. Insomnia did not predict incident hypertension in older adults in the Cardiovascular Health Study. Sleep. 2009;32(1):65–72. doi:10.5665/sleep/32.1.65
20. Sforza E, Saint Martin M, Barthelemy JC, Roche F. Association of self-reported sleep and hypertension in noninsomniac elderly subjects. J Clin Sleep Med. 2014;10(9):955–71. doi:10.5664/jcsm.4026
21. Thomas SJ, Calhoun D. Sleep, insomnia, and hypertension: current findings and future directions. J Am Soc Hypertens. 2017;11(2):122–9. doi:10.1016/j.jash.2016.11.008
22. Castro-Diehl C, Diez Roux A V., Redline S, Seeman T, McKinley P, Sloan R, et al. Sleep duration and quality in relation to autonomic nervous system measures: the multi-ethnic study of atherosclerosis (MESA). Sleep. 2016;39(11):1927–40. doi:10.5665/sleep.6218
23. Yamashita A, Hamada A, Suhara Y, Kawabe R, Yanase M, Kuzumaki N, et al. Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. Synapse. 2014;68(6):235–47. doi:10.1002/syn.21733
24. Guadagni V, Burles F, Ferrara M, Iaria G. Sleep quality and its association with the insular cortex in emotional empathy. Eur J Neurosci. 2018;48(6):2288–300. doi:10.1111/ejn.14124
25. Ono D, Yamanaka A. Hypothalamic regulation of the sleep/wake cycle. Neurosci Res. 2017;118:74–81. doi:10.1016/j.neures.2017.03.013
26. Coote JH, Spyer KM. Central control of autonomic function. Brain and Neuroscience Advances. 2018;2:239821281881201. doi:10. 1177/2398212818812012
27. Li Y, Vgontzas AN, Fernandez-Mendoza J, Bixler EO, Sun Y, Zhou J, et al. Insomnia with physiological hyperarousal is associated with hypertension. Hypertension. 2015;65:644–50. doi:10.1161/HYPERTENSIONAHA.114.04604
28. Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science. Sleep Med Rev. 2010;14(1):9–15. doi:10.1016/j.smrv.2009.05.002
29. Chen GH, Xia L, Wang F, Li XW, Jiao CA. Patients with chronic insomnia have selective impairments in memory that are modulated by cortisol. Psychophysiology. 2016;53(10):1567–76. doi:10.1111/psyp.12700
30. DiBona GF. Sympathetic nervous system, diabetes, and hypertension. Hypertension. 2013;61:556–60. doi:10.1081/CEH‑100001196
31. Lanfranchi PA, Pennestri MH, Fradette L, Dumont M, Morin CM, Montplaisir J. Nighttime blood pressure in normotensive subjects with chronic insomnia: Implications for cardiovascular risk. Sleep. 2009;32(6):760–6. doi:10.1093/sleep/32.6.760
32. Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory hypertension: evidence of heightened activity as a cause of antihypertensive treatment failure. Hypertension. 2015;66(1):126–33. doi:10.1161/HYPERTENSIONAHA.115.05449.REFRACTORY
33. Portaluppi F, Tiseo R, Smolensky MH, Hermida RC, Ayala DE, Fabbian F. Circadian rhythms and cardiovascular health. Sleep Med Rev. 2012;16(2):151–66. doi:10.1016/jsmrv.2011.04.003
34. Crnko S, Du Pré BC, Sluijter JPG, Van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol. 2019; doi:10.1038/s41569-019-0167-4
35. Одинак М. М., Денищук И. С. Особенности суточного профиля артериального давления у больных с прогредиентным течением гипертонической дисциркуляторной энцефалопатии. Вестник Российской Военно-медицинской академии. 2006; 2(16):26–9.
36. Одинак М. М., Хубулава Г. Г., Кузнецов А. Н., Вознюк И. А., Арсенова Н. А. Коррекция нарушения церебральной гемодинамики при артериальной гипертензии с помощью современных ингибиторов ангиотензин-превращающего фермента. Артериальная гипертензия. 2006;12(4):347–50.
37. Тихомирова О. В., Машкова Н. П., Маматова Н. Т., Котлярова Е. В., Сорокоумов В. А. Допплерографическая диагностика функционального состояния мозгового кровообращения при лакунарных инфарктах и артериальной гипертензии. Артериальная гипертензия. 2003;9(5):174–7.
38. Ga̧secki D, Kwarciany M, Nyka W, Narkiewicz K. Hypertension, brain damage and cognitive decline. Curr Hypertens Rep. 2013;15(6):547–58. doi:10.1007/s11906-013-0398-4
39. Amenta F, Di Tullio MA, Tomassoni D. Arterial hypertension and brain damage — evidence from animal models. Clin Exp Hypertens. 2003;25(6):359–80. doi:10.1081/CEH‑120023545
40. Sierra C, Doménech M, Camafort M, Coca A. Hypertension and mild cognitive impairment. Current Hypertension Reports. 2012;14(6):548–55. doi:10.1007/s11906-012-0315-2
41. Porter VR, Buxton WG, Avidan AY. Sleep, Cognition and dementia. Current Psychiatry Reports. 2015;17(97):1–11. doi:10.1007/s11920-015-0631-8
42. Reid KJ, Baron KG, Lu B, Naylor E. Changes in cognitive performance are associated with changes in sleep in older adults with insomnia. Behav Sleep Med. 2016;14(3):295–310. doi:10.1016/j.sleep.2010.04.014.Aerobic
43. Zhang P, Tan C‑W, Chen G‑H, Ge Y‑J, Xu J, Xia L, et al. Patients with chronic insomnia disorder have increased serum levels of neurofilaments, neuron-specific enolase and S100B: does organic brain damage exist? Sleep Medicine. 2018;48:163–71. doi:https://doi.org/10.1016/j.sleep.2017.12.012
44. Joo EY, Noh HJ, Kim J‑S, Koo DL, Kim D, Hwang KJ, et al. Brain gray matter deficits in patients with chronic primary insomnia. Sleep. 2013;36(7):999–1007. doi:10.5665/sleep.2796
45. O’Byrne JN, Berman Rosa M, Gouin JP, Dang-Vu TT. Neuroimaging findings in primary insomnia. Pathologie Biologie. 2014;62(5):262–9. doi:10.1016/j.patbio.2014.05.013
46. Spiegelhalder K, Regen W, Prem M, Baglioni C, Nissen C, Feige B, et al. Reduced anterior internal capsule white matter integrity in primary insomnia. Human Brain Mapping. 2014;35(7): 3431–8. doi:10.1002/hbm.22412
47. Drake CL, Pillai V, Roth T. Stress and sleep reactivity: a prospective investigation of the stress-diathesis model of insomnia. Sleep. 2014;37(8):1295–304. doi:10.5665/sleep.3916
48. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. The Psychiatric clinics of North America. 1987;10(4):541–53.
49. Xanthos DN, Sandkühler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nature Rev Neurosci. 2014;15(1):43–53. doi:10.1038/nrn3617
50. Rohleder N, Aringer M, Boentert M. Role of interleukin‑6 in stress, sleep, and fatigue. Annals of the New York Academy of Sciences. 2012;1261(1):88–96. doi:10.1111/j.1749-6632.2012.06634.x
51. Hurtado-Alvarado G, Dominguez-Salazar E, Pavon L, Velazquez-Moctezuma J, Gomez-Gonzalez B. Blood-brain barrier disruption induced by chronic sleep loss: low-grade inflammation may be the link. J Immunol Res. 2016;2016 (4576012):1–15. doi:10.1155/2016/4576012
52. Heinzelmann M, Lee H, Rak H, Livingston W, Barr T, Baxter T, et al. Sleep restoration is associated with reduced plasma C‑reactive protein and depression symptoms in military personnel with sleep disturbance after deployment. Sleep Med. 2014;15 (12):1565–70. doi:10.1016/j.sleep.2014.08.004
53. Erta M, Quintana A, Hidalgo J. Interleukin‑6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8(9): 1254–66. doi:10.7150/ijbs.4679
54. Benedict C, Scheller J, Rose-John S, Born J, Marshall L. Enhancing influence of intranasal interleukin‑6 on slow-wave activity and memory consolidation during sleep. The FASEB J. 2009;23(10):3629–36. doi:10.1096/fj.08–122853
55. Burgos I, Richter L, Klein T, Fiebich B, Feige B, Lieb K, et al. Increased nocturnal interleukin‑6 excretion in patients with primary insomnia: a pilot study. Brain, Behavior, and Immunity. 2006;20(3):246–53. doi:10.1016/j.bbi.2005.06.007
56. Vgontzas AN, Zoumakis M, Papanicolaou DA, Bixler EO, Prolo P, Lin HM, et al. Chronic insomnia is associated with a shift of interleukin‑6 and tumor necrosis factor secretion from nighttime to daytime. Metabolism. 2002;51(7):887–92. doi:10.1053/meta.2002.33357
57. Irwin MR, Olmstead R, Breen EC, Witarama T, Carrillo C, Sadeghi N, et al. Tai Chi, cellular inflammation, and transcriptome dynamics in breast cancer survivors with insomnia: A randomized controlled trial. J Nat Cancer Institute. 2014;2014 (50):295–301. doi:10.1093/jncimonographs/lgu028
58. Irwin MR, Olmstead R, Breen EC, Witarama T, Carrillo C, Sadeghi N, et al. Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: a randomized controlled trial. Biological Psychiatry. 2015;78(10): 721–9. doi:10.1016/j.biopsych.2015.01.010
59. Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. BioMed Research International. 2014;2014 (406960): 1–11. doi:10.1155/2014/406960
60. Chamarthi B, Williams GH, Ricchiuti V, Srikumar N, Hopkins PN, Luther JM, et al. Inflammation hypertension: the interplay of interleukin‑6, dietary sodium and the reninangiotensin system in humans. Am J Hypertens. 2011;24(10):1–13. doi:10.1038/ajh.2011.113.Inflammation
61. Hashmat S, Rudemiller N, Lund H, Abais-Battad JM, Van Why S, Mattson DL. Interleukin‑6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats. Am J Renal Physiol. 2016;311 (3):555–61. doi:10.1152/ajprenal.00594.2015
62. Heijnen BFJ, Van Essen H, Schalkwijk CG, Janssen BJA, Struijker-Boudier HAJ. Renal inflammatory markers during the onset of hypertension in spontaneously hypertensive rats. Рнзукеу-ты Куы. 2014;37(2):100–9. doi:10.1038/hr.2013.99
63. Rodriguez-Iturbe B, Johnson RJ. Role of inflammatory cells in the kidney in the induction and maintenance of hypertension. Nephrology Dialysis Transplantation. 2006;21(2):260–3. doi:10.1093/ndt/gfi319
64. Mao SQ, Sun JH, Gu TL, Zhu FB, Yin FY, Zhang LN. Hypomethylation of interleukin‑6 (IL‑6) gene increases the risk of essential hypertension: a matched case-control study. J Hum Hypertens. 2017;31(8):530–6. doi:10.1038/jhh.2017.7
65. Tamura Y, Phan C, Tu L, Le Hiress M, Thuillet R, Jutant EM, et al. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. JJ Clin Invest. 2018;128(5):1956–70. doi:10.1172/JCI96462
66. Schölzel BE, Post MC, Dymarkowski S, Wuyts W, Meyns B, Budts W, et al. Plasma interleukin‑6 adds prognostic information in pulmonary arterial hypertension. Eur Resp J. 2014;43(3):909–12. doi:10.1183/09031936.00174113
67. Pullamsetti SS, Seeger W, Savai R. Classical IL‑6 signaling: a promising therapeutic target for pulmonary arterial hypertension. J Clin Invest. 2018;128(5):1720–3. doi:10.1172/JCI120415
68. Gottesmann C. GABA mechanisms and sleep. Neuroscience. 2002;111(2):231–9. doi:10.1016/S0306-4522(02)00034-9
69. Plante DT, Jensen JE, Schoerning L, Winkelman JW. Reduced γ-aminobutyric acid in occipital and anterior cingulate cortices in primary insomnia: a link to major depressive disorder. Neuropsychopharmacology. 2012;37(6):1548–57. doi:10.1038/npp.2012.4
70. Winkelman, Buxton, Jensen, Benson, O’Connor, Wang C et al. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep. 2008;31(11):1499–506.
71. Chen HH, Cheng PW, Ho WY, Lu PJ, Lai CC, Tseng YM, et al. Renal denervation improves the baroreflex and GABA system in chronic kidney disease-induced hypertension. Scientific Reports. 2016;6(38447):1–13. doi:10.1038/srep38447
72. Ma P, Li T, Ji F, Wang H, Pang J. Effect of GABA on blood pressure and blood dynamics of anesthetic rats. Int J Clin Exp Med. 2015;8(8):14296–302.
73. Mei L, Zhang J, Mifflin S. Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract. Am J Physiology-Regulatory, Integrative and Comparative Physiology. 2003;285(6):1276–86. doi:10.1152/ajpregu.00255.2003
74. Shimada M, Hasegawa T, Nishimura C, Kan H, Kanno T, Nakamura T, et al. Anti-hypertensive effect of gamma-aminobutyric acid (GABA) rich Chlorella on high normal blood pressure and borderline hypertension in placebo-controlled double blind study. J Clin Exp Hypertens. 2019;31(4):342–54.
75. Byun JI, Shin YY, Chung SE, Shin WC. Safety and efficacy of gamma-aminobutyric acid from fermented rice germ in patients with insomnia symptoms: A randomized, double-blind trial. J Clin Neurol (Korea). 2018;14(3):291–5. doi:10.3988/jcn.2018.14.3.291
76. Ursavas A. Upregulating substance P levels to treat obstructive sleep apnea. Expert Opinion on Therapeutic Targets. 2008;12(5):583–8. doi:10.1517/14728222.12.5.583
77. Wang Y, Wang DH. Role of substance P in renal injury during DOCA-salt hypertension. Endocrinology. 2012;153 (12):5972–9. doi:10.1210/en.2012-1284
78. Ratti E, Carpenter DJ, Zamuner S, Fernandes S, Squassante L, Danker-Hopfe H, et al. Efficacy of vestipitant, a neurokinin‑1 receptor antagonist, in primary insomnia. Sleep. 2013;36(12):1823–30. doi:10.5665/sleep.3208
79. Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis & Rheumatism. 1994;37(11):1593–601. doi:10.1002/art.1780371106
80. Lieb K, Ahlvers K, Dancker K, Strohbusch S, Reincke M, Feige B, et al. Effects of the neuropeptide substance P on sleep, mood, and neuroendocrine measures in healthy young men. Neuropsychopharmacology. 2002;27(6):1041–9. doi:10.1016/S0893-133X(02)00369‑X
81. Schwartz TL, Goradia V. Managing insomnia: An overview of insomnia and pharmacologic treatment strategies in use and on the horizon. Drugs in Context. 2013;1–10. doi:10.7573/dic.212257
82. Kohlmann O, Cesaretti ML, Ginoza M, Tavares A, Zanella MT, Ribeiro AB, et al. Role of substance P in blood pressure regulation in salt-dependent experimental hypertension. Hypertension. 1997;29(1):506–9. doi:10.1161/01.hyp.29.1.506
83. Faulhaber HD, Oehme P, Baumann R, Enderlein J, Rathsack R, Rostock G, et al. Substance P in human essential hypertension. J Cardiovasc Pharmacol. 2008;10 (Sup 12):172–6. doi:10.1097/00005344-198710012-00029
84. Mori K, Asakura S, Ogawa H, Sasagawa S, Takeyama M. Decreases in Substance P and vasoactive intestinal peptide concentrations in plasma of stroke-prone spontaneously hypertensive rats. Jap Heart J. 1993;34(6):785–94. doi:10.1536/ihj.34.785
85. Dehlin HM, Manteufel EJ, Monroe AL, Reimer MHJ, Levick SP. Substance P acting via the neurokinin‑1 receptor regulates adverse myocardial remodeling in a rat model of hypertension. Int J Cardiol. 2013;168(5):4643–4651. doi:10.1007/s00246-012-0450-1.A
86. Meléndez GC, Li J, Law BA, Janicki JS, Supowit SC, Levick SP. Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res. 2011;92(3):420–9. doi:10.1093/cvr/cvr244
87. Chen L‑W, Chen C‑F, Lai Y‑L. Chronic activation of neurokinin‑1 receptor induces pulmonary hypertension in rats. Am J Physiol. 1999;276(5):1543–51. doi:10.1152/ajpheart.1999.276.5.h1543
88. Katsi V, Karagiorgi I, Makris T, Papavasileiou M, Androulakis AE, Tsioufis C, et al. The role of melatonin in hypertension. Cardiovasc Endocrinol. 2012;1(1):13–8. doi:10.1097/xce.0b013e3283565783
89. Grossman E. Should melatonin be used to lower blood pressure? Hypertens Res. 2013;36(8):682–3. doi:10.1038/hr.2013.29
90. Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vascular Health and Risk Management. 2011;7(1):577–84. doi:10.2147/VHRM.S24603
91. Hajak G, Rodenbeck A, Staedt J, Bandelow B, Huether G, Rüther E. Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia. J Pineal Res. 1995;19(3):116–22. doi:10.1111/j.1600-079X.1995.tb00179.x
92. Niederhofer H, Staffen W, Mair A, Pittschieler K. Melatonin facilitates sleep in individuals with mental retardation and insomnia. J Autism Developmental Disorders. 2003;33(4):469–72. doi:10.1023/A:1025027231938
93. Grima NA, Rajaratnam SMW, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: A randomised controlled trial. BMC Medicine. 2018;16(1):1–10. doi:10.1186/s12916-017-0995-1
94. Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Current Medical Research and Opinion. 2007;23 (10):2597–605. doi:10.1185/030079907X233098
95. Van Maanen A, Meijer AM, Smits MG, Van Der Heijden KB, Oort FJ. Effects of melatonin and bright light treatment in childhood chronic sleep onset insomnia with late melatonin onset: a randomized controlled study. Sleep. 2017; 40(2):1–11. doi:10.1093/sleep/zsw038
96. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(3):307–49. doi:10.5664/jcsm.6506
97. Fraer M, Kilic F. Serotonin: a different player in hypertensionassociated thrombosis. Hypertension. 2015;65(5):942–8. doi:10.1161/HYPERTENSIONAHA.114.05061
98. Cespuglio R. Serotonin: its place today in sleep preparation, triggering or maintenance. Sleep Med. 2018;(49):31–9. doi:10.1016/j.sleep.2018.05.034
99. Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15(4):269–81. doi:10.1016/j.smrv.2010.11.003
100. Murray NM, Buchanan GF, Richerson GB. Insomnia caused by serotonin depletion is due to hypothermia. Sleep. 2015;38 (12):1985–93. doi:10.5665/sleep.5256
101. Shabbir F, Patel A, Mattison C, Bose S, Krishnamohan R, Sweeney E et al. Effect of diet on serotonergic neurotransmission in depression. Neurochem Int. 2013:62:324–39. doi:10.1016/j.neuint.2012.12.014
102. Wang L, Zhou C, Zhu D, Wang X, Fang L, Zhong J, et al. Serotonin‑1A receptor alterations in depression: a meta-analysis of molecular imaging studies. BMC Psychiatry. 2016;16(1):1–9. doi:10.1186/s12888-016-1025-0
103. Baranyi A, Amouzadeh-Ghadikolai O, Rothenhäusler HB, Theokas S, Robier C, Baranyi M, et al. Nitric oxide-related biological pathways in patients with major depression. PLoS ONE. 2015;10(11):1–15. doi:10.1371/journal.pone.0143397
104. Watts SW, Morrison SF, Davis RP, Barman SM. Serotonin and blood pressure regulation. Pharmacol Rev. 2012;64(2):359–88. doi:10.1124/pr.111.004697
105. Razavi BM, Hosseinzadeh H. A review of the role of orexin system in pain modulation. Biomed Pharmacother. 2017;90:187–93. doi:10.1016/j.biopha.2017.03.053
106. Rani M, Kumar R, Krishan P. Implicating the potential role of orexin in hypertension. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2017;390(7):667–76. doi:10.1007/s00210-017-1378‑z
107. Rani M, Kumar R, Krishan P. Role of orexins in the central and peripheral regulation of glucose homeostasis: evidences & mechanisms. Neuropeptides. 2018;68:1–6. doi:10.1016/j.npep.2018.02.002
108. Inutsuka A, Yamanaka A. The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Frontiers in Endocrinology. 2013; 4:1–10. doi:10.3389/fendo.2013.00018
109. Silvani A. Orexins and the cardiovascular events of awakening. Temperature. 2017;4(2):128–40. doi:10.1080/23328940.2017.1295128
110. Prober DA, Rihel J, Onah AA, Sung R‑J, Schier AF. Hypocretin/Orexin overexpression induces an insomnia-like phenotype in zebrafish. J Neurosci. 2006;26 (51):13400–10. doi:10.1523/JNEUROSCI.4332–06.2006
111. Tang S, Huang W, Lu S, Lu L, Li G, Chen X, et al. Increased plasma orexin-A levels in patients with insomnia disorder are not associated with prepro-orexin or orexin receptor gene polymorphisms. Peptides. 2017;88:55–61. doi:10.1016/j.peptides.2016.12.008
112. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kanna H. Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol. 1999;277(6):1780–5.
113. Li A, Hindmarch CCT, Nattie EE, Paton JFR. Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. J Physiol. 2013;591(17):4237–48 doi:10.1113/jphysiol.2013.256271
114. Clifford L, Dampney BW, Carrive P. Spontaneously hypertensive rats have more orexin neurons in their medial hypothalamus than normotensive rats. Exp Physiol. 2015;100(4):388–98. doi:10.1113/expphysiol.2014.084137
115. Schwimmer H, Stauss HM, Abboud F, Nishino S, Mignot E, Zeitzer JM. Effects of sleep on the cardiovascular and thermoregulatory systems: a possible role for hypocretins. J App Physiol. 2010;109(4):1053–63. doi:10.1152/japplphysiol.00516.2010
116. Berteotti C, Silvani A. The link between narcolepsy and autonomic cardiovascular dysfunction: a translational perspective. Clinical Autonomic Research. 2018;28(6):545–55. doi:10.1007/s10286-017-0473‑z
117. Li A, Nattie E. Orexin, cardio-respiratory function, and hypertension. Frontiers in Neuroscience. 2014;8:1–18. doi:10.3389/fnins.2014.00022
118. Bathgate CJ, Fernandez-Mendoza J. Insomnia, short sleep duration, and high blood pressure: recent evidence and future directions for the prevention and management of hypertension. Curr Hypertens Rep. 2018;20(52):1–9. doi:10.1007/s11906-018-0850-6