Skip to main content
Log in

Dose-Dependent Mechanisms of Melatonin on the Functioning of the Cardiovascular System and on the Behavior of Normotensive Rats of Different Ages

  • Published:
Advances in Gerontology Aims and scope Submit manuscript

Abstract

The purpose of the work on normotensive rats of different age groups (3, 15, and 22 months) is to study the synchronism between the functioning of the cardiovascular system and the locomotor activity of animals in open field tests by a single injection of exogenous melatonin in different doses (1 and 10 mg/kg). The studies show a unidirectional dose-dependent effect of exogenous melatonin on the locomotor activity of rats of different ages and an age-dependent effect of melatonin on the parameters of the cardiovascular system. The results show the possible desynchronization between the circadian rhythms of locomotor activity and the functioning of the cardiovascular system with aging, which can lead to a discrepancy between hemodynamic parameters and the level of locomotor activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.

Similar content being viewed by others

REFERENCES

  1. Anisimov, V.N., Epiphysis, biorhythms, and aging of an organism, Usp. Fiziol. Nauk, 2008, vol. 39, no. 4, pp. 40–65.

    CAS  PubMed  Google Scholar 

  2. Arushanyan, E.B. and Popov, A.V., Modern concepts on the role of the suprachiasmatic nuclei of the hypothalamus in the organization of diurnal periodism of physiological functions, Usp. Fiziol. Nauk, 2011, vol. 42, no. 4, pp. 39–58.

    Google Scholar 

  3. Beier, E.V. and Skornyakov, A.A., Comparative assessment of psychotropic activity of melatonin on various behavioral models, Trudy X Mezhdunarodnogo kongressa “Zdorov’e i obrazovanie XXI veka” (Proc. X Int. Congr. “Health and Education in 21st Century”), Moscow, 2011, vol. 13, no. 7, p. 319.

  4. Beier, E.V., Skornyakov, A.A., and Arushanyan, E.B., Effect of pineal gland removal on the psychotropic activity of adaptogenic agents in rats, Med. Vestn. Sev. Kavk., 2014, vol. 9, no. 3, pp. 254–258.

    Google Scholar 

  5. Kim, L.B., Putyatina, A.N., Russkikh, G.S., and Tsypysheva, O.B., Melatonin and the aging process in men in the European part of the Arctic zone of Russia, Adv. Gerontol., 2019, vol. 9, no. 1, pp. 67–74.

    Article  Google Scholar 

  6. Kurbatova, I.V., Topchieva, L.V., and Nemov, N.N., Circadian genes and cardiovascular pathologies, Tr. Karel. Nauchn. Tsentra, Ross. Akad. Nauk, 2014, no. 5, pp. 3–17.

  7. American Heart Association, Heart rate variability: standards of measurement, physiological interpretation, and clinical use, Circulation, 1996, vol. 93, no. 5, pp. 1043–1065.

  8. Acuña-Castroviejo, D., Escames, G., Venegas, C., et al., Extra pineal melatonin: sources, regulation, and potential functions, Cell Mol. Life Sci., 2014, vol. 71, no. 16, pp. 2997–3025.

  9. Adamsson, M., Laike, T., and Morita, T., Annual variation in daily light exposure and circadian change of melatonin and cortisol concentrations at a northern latitude with large seasonal differences in photoperiod length, J. Physiol. Anthropol., 2016, vol. 36, no. 1, p. 6. https://doi.org/10.1186/s40101-016-0103-9

    Article  PubMed  PubMed Central  Google Scholar 

  10. Arendt, J., Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology, Rev. Reprod., 1998, vol. 3, pp. 13–22.

    Article  CAS  PubMed  Google Scholar 

  11. Atkinson, G., Witte, K., Nold, G., et al., Effects of age on circadian blood pressure and heart rate rhythms in patients with primary hypertension, Chronobiol. Int., 1994, vol. 11, no. 1, pp. 35–44.

    Article  CAS  PubMed  Google Scholar 

  12. Benloucif, S., Masana, M.I., and Dubocovich, M.L., Responsiveness to melatonin and its receptor expression in the aging circadian clock of mice, Am. J. Physiol., 1997, vol. 273, no. 6, pp. R1855– R1860.

    CAS  PubMed  Google Scholar 

  13. Bilan, A., Witczak, A., Palusiński, R., et al., Circadian rhythm of spectral indices of heart rate variability in healthy subjects, J. Electrocardiol., 2005, vol. 38, no. 3, pp. 239–243.

    Article  PubMed  Google Scholar 

  14. Campos Costa, I., Nogueira Carvalho, H., and Fernandes, L., Aging, circadian rhythms and depressive disorders: a review, Am. J. Neurodegener. Dis., 2013, vol. 2, no. 4, pp. 228–246.

    PubMed  PubMed Central  Google Scholar 

  15. Cheung, R.T., Tipoe, G.L., Tam, S., et al., Preclinical evaluation of pharmacokinetics and safety of melatonin in propylene glycol for intravenous administration, J. Pineal Res., 2006, vol. 41, no. 4, pp. 337–343.

    Article  CAS  PubMed  Google Scholar 

  16. Chuang, J.I. and Lin, M.T., Pharmacological effects of melatonin treatment on both locomotor activity and brain serotonin release in rats, J. Pineal Res., 1994, vol. 17, no. 1, pp. 11–16.

    Article  CAS  PubMed  Google Scholar 

  17. Douma, L.G. and Gumz, M.L., Circadian clock-mediated regulation of blood pressure, Free Radical Biol. Med., 2018, vol. 119, pp. 108–114.

    Article  CAS  Google Scholar 

  18. Dubocovich, M.L., Melatonin receptors: Are there multiple subtypes?, Trends Pharmacol. Sci., 1995, vol. 16, pp. 50–56.

    Article  CAS  PubMed  Google Scholar 

  19. Emet, M., Ozcan, H., Ozel, L., et al., A review of melatonin, its receptors and drugs, Eurasian J. Med., 2016, vol. 48, no. 2, pp. 135–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Evans, B.K., Mason, R., and Wilson, V.G., Evidence for direct vasoconstrictor activity of melatonin in “pressurized” segments of isolated caudal artery from juvenile rats, Naunyn-Schmiedeberg’s Arch. Pharmacol., 1992, vol. 346, no. 3, pp. 362–365.

    Article  CAS  Google Scholar 

  21. Franchini, K., Moreira, E.D., Ida, F., and Krieger, E.M., Alterations in the cardiovascular control by the chemoreflex and the baroreflex in old rats, Am. J. Physiol.-Regul., Integr. Comp. Physiol., 1996, vol. 270, pp. R310–R313.

    Article  CAS  Google Scholar 

  22. Gupta, A.K., Cornelissen, G., Greenway, F.L., et al., Abnormalities in circadian blood pressure variability and endothelial function: pragmatic markers for adverse cardiometabolic profiles in asymptomatic obeseadults, Cardiovasc. Diabetol., 2010, vol. 9, p. 58. https://doi.org/10.1186/1475-2840-9-58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grossman, E., Laudon, M., and Zisapel, N., Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials, Vasc. Health Risk Manage., 2011, vol. 7, pp. 577–584.

    CAS  Google Scholar 

  24. Hall, C.S., Emotional behavior in the rat. III. The relationship between emotionality and ambulatory activity, J. Comp. Physiol. Psychol., 1936, vol. 22, pp. 345–352.

    Article  Google Scholar 

  25. Hashimoto, M., Kuwahara, M., Tsubone, H., and Sugano, S., Diurnal variation of autonomic nervous activity in the rat: investigation by power spectral analysis of heart rate variability, J. Electrocardiol., 1999, vol. 32, no. 2, pp. 167–171.

    Article  CAS  PubMed  Google Scholar 

  26. Huang, L., Zhang, C., Hou, Y., et al., Blood pressure reducing effects of piromelatine and melatonin in spontaneously hypertensive rats, Eur. Rev. Med. Pharmacol. Sci., 2013, vol. 17, no. 18, pp. 2449–2456.

    CAS  PubMed  Google Scholar 

  27. Hutchinson, A.J., Hudson, R.L., and Dubocovich, M.L., Genetic deletion of MT(1) and MT(2) melatonin receptors differentially abrogates the development and expression of methamphetamine-induced locomotor sensitization during the day and the night in C3H/HeN mice, J. Pineal Res., 2012, vol. 53, no. 4, pp. 399–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jenwitheesuk, A., Boontem, P., Wongchitrat, P., et al., Melatonin regulates the aging mouse hippocampal homeostasis via the sirtuin1-FOXO1 pathway, EXCLI J., 2017, vol. 16, pp. 340–353.

    PubMed  PubMed Central  Google Scholar 

  29. Jiki, Z., Lecour, S., and Nduhirabandi, F., Cardiovascular benefits of dietary melatonin: a myth or a reality?, Front. Physiol., 2018, vol. 17, no. 9, p. 528. https://doi.org/10.3389/fphys.2018.00528

    Article  Google Scholar 

  30. Korpelainen, J.T., Sotaniemi, K.A., Huikuri, H.V., and Myllylä, V.V., Circadian rhythm of heart rate variability is reversibly abolished in ischemic stroke, Stroke, 1997, vol. 28, no. 11, pp. 2150–2154.

    Article  CAS  PubMed  Google Scholar 

  31. Laudon, M., Nir, I., and Zisapel, N., Melatonin receptors in discrete brain areas of the male rat. Impact of aging on density and on circadian rhythmicity, Neuroendocrinology, 1988, vol. 48, no. 6, pp. 577–583.

    Article  CAS  PubMed  Google Scholar 

  32. Lew, M.J. and Flanders, S., Mechanisms of melatonin-induced vasoconstriction in the rat tail artery: a paradigm of weak vasoconstriction, Br. J. Pharmacol., 1999, vol. 126, no. 6, pp. 1408–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lindesay, G., Ragonnet, C., Chimenti, S., et al., Age and hypertension strongly induce aortic stiffening in rats at basal and matched blood pressure levels, Physiol. Rep., 2016, vol. 4, no. 10, p. e12805. https://doi.org/10.14814/phy2.12805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, J., Clough, S.J., Hutchinson, A.J., et al., Mt1 and Mt2 melatonin receptors: a therapeutic perspective, Ann. Rev. Pharmacol. Toxicol., 2016, vol. 56, pp. 361–383.

    Article  CAS  Google Scholar 

  35. Lusardi, P., Piazza, E., and Fogari, R., Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study, Br. J. Clin. Pharmacol., 2000, vol. 49, pp. 423–427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mattam, U. and Jagota, A., Differential role of melatonin in restoration of age-induced alterations in daily rhythms of expression of various clock genes in suprachiasmatic nucleus of male Wistar rats, Biogerontology, 2014, vol. 15, no. 3, pp. 257–268.

    Article  CAS  PubMed  Google Scholar 

  37. Ng, K.Y., Leong, M.K., Liang, H., and Paxinos, G., Melatonin receptors: distribution in mammalian brain and their respective putative functions, Brain Struct. Funct., 2017, vol. 222, no. 7, pp. 2921–2939.

    Article  CAS  PubMed  Google Scholar 

  38. Nishiyama, K., Yasue, H., Moriyama, Y., et al., Acute effects of melatonin administration on cardiovascular autonomic regulation in healthy men, Am. Heart J., 2001, vol. 141, no. 5, p. E9. https://doi.org/10.1067/mhj.2001.114368

    Article  CAS  PubMed  Google Scholar 

  39. Pechanova, O., Zicha, J., Paulis, L., et al., The effect of N-acetyl cysteine and melatonin in adult spontaneously hypertensive rats with established hypertension, Eur. J. Pharmacol., 2007, vol. 561, nos. 1–3, pp. 129–136.

  40. Pechanova, O., Paulis, L., and Simko, F., Peripheral and central effects of melatonin on blood pressure regulation, Int. J. Mol. Sci., 2014, vol. 15, no. 10, pp. 17920–17937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pfeffer, M., Korf, H.W., and Wicht, H., The role of the melatoninergic system in light-entrained behavior of mice, Int. J. Mol. Sci., 2017, vol. 18, no. 3, p. E530.

    Article  CAS  PubMed  Google Scholar 

  42. Rajendra, A.U., Paul, J.K., Kannathal, N., et al., Heart rate variability: a review, Med. Bio Eng. Comput., 2006, vol. 44, no. 12, pp. 1031–1051.

    Article  Google Scholar 

  43. Romerowicz-Misielak, M., Oren, D.A., Sowa-Kucma, M., et al., Changes in melatonin synthesis parameters after carbon monoxide concentration increase in the cavernous sinus, J. Physiol. Pharmacol., 2015, vol. 66, no. 4, pp. 505–514.

    CAS  PubMed  Google Scholar 

  44. Rosenthal, T., Seasonal variations in blood pressure, Am. J. Geriatr. Cardiol., 2004, vol. 13, no. 5, pp. 267–272.

    Article  PubMed  Google Scholar 

  45. Rossi, S., Fortunati, I., Carnevali, L., et al., The effect of aging on the specialized conducting system: a telemetry ECG study in rats over a 6month period, PLoS One, 2014, vol. 9, no. 11, p. e112697. https://doi.org/10.1371/journal.pone.0112697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sánchez-Hidalgo, M., Guerrero Montavez, J.M., Carrascosa-Salmoral Mdel, P., et al., Decreased MT1 and MT2 melatonin receptor expression in extrapineal tissues of the rat during physiological aging, J. Pineal Res., 2009, vol. 46, no. 1, pp. 29–35.

  47. Sei, H., Sano, A., Ohno, H., et al., Age-related changes in control of blood pressure and heart rate during sleep in the rat, Sleep, 2002, vol. 25, no. 3, pp. 279–285.

    Article  PubMed  Google Scholar 

  48. Vandeputte, C., Giummelly, P., Atkinson, J., et al., Melatonin potentiates NE-induced vasoconstriction without augmenting cytosolic calcium concentration, Am. J. Physiol. Heart Circ. Physiol., 2001, vol. 280, no. 1, pp. H420–H425.

    Article  CAS  PubMed  Google Scholar 

  49. Waki, H., Katahira, K., Polson, J.W., et al., Automation of analysis of cardiovascular autonomic function from chronic measurements of arterial pressure in conscious rats, Exp. Physiol., 2006, vol. 91, no. 1, pp. 201–213.

    Article  PubMed  Google Scholar 

  50. Watanabe, Y., Toyoshima, T., Otsuka, K., et al., Circadian profiles of blood pressure with respect to age, Nihon Ronen Igakkai Zasshi, 1994, vol. 31, no. 3, pp. 219–225.

    Article  CAS  PubMed  Google Scholar 

  51. Weekley, L.B., Melatonin-induced relaxation of rat aorta: interaction with adrenergic agonists, J. Pineal Res., 1991, vol. 11, no. 1, pp. 28–34.

    Article  CAS  PubMed  Google Scholar 

  52. Wu, Y.H. and Swaab, D.F., The human pineal gland and melatonin in aging and Alzheimer’s disease, Pineal Res., 2005, vol. 38, no. 3, pp. 145–152.

    Article  CAS  Google Scholar 

  53. Yeleswaram, K., McLaughlin, L.G., Knipe, J.O., and Schabdach, D., Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications, J. Pineal Res., 1997, vol. 22, no. 1, pp. 45–51.

    Article  CAS  PubMed  Google Scholar 

  54. Zaretsky, D.V., Zaretskaia, M.V., and DiMicco, J.A., Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats, Physiol. Behav., 2016, vol. 154, pp. 60–67.

    Article  CAS  PubMed  Google Scholar 

  55. Zhao, T., Zhang, H., Jin, C., et al., Melatonin mediates vasodilatation through both direct and indirect activation of BKC channels, J. Mol. Endocrinol., 2017, vol. 59, no. 3, pp. 219–233.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. V. Kuzmenko.

Ethics declarations

Conflict of interest. The authors delate that they have no conflict of interest.

Statement on the welfare of animals. The conditions of the research were in accordance with the ethical standards of the Almazov National Medical Research Centre (St. Petersburg), European Communities Council Directive 1986 (86/609/ EEC), and the rules stated in the Guide for the Care and Use of Laboratory Animals.

This study does not contain any studies involving human participants performed by any of the authors.

Additional information

Translated by M. Novikova

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pliss, M.G., Kuzmenko, N.V., Rubanova, N.S. et al. Dose-Dependent Mechanisms of Melatonin on the Functioning of the Cardiovascular System and on the Behavior of Normotensive Rats of Different Ages. Adv Gerontol 9, 327–335 (2019). https://doi.org/10.1134/S2079057019030111

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S2079057019030111

Keywords:

Navigation