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Aerobic exercise enhanced endothelium-dependent vasorelaxation in mesenteric arteries in spontaneously hypertensive rats: the role of melatonin

Abstract

Melatonin, a neuroendocrine hormone synthesized primarily by the pineal gland, provides various cardiovascular benefits. Regular physical activity is an effective non-pharmacological therapy for the prevention and control of hypertension. In the present study, we hypothesized that melatonin plays an important role in the aerobic exercise-induced increase of endothelium-dependent vasorelaxation in the mesenteric arteries (MAs) of spontaneously hypertensive rats (SHRs) in a melatonergic receptor-dependent manner. To test this hypothesis, we evaluated the vascular mechanical and functional properties in normotensive Wistar Kyoto (WKY), SHRs, and SHRs that were trained on a treadmill (SHR-EX) for 8 weeks. Exercise training produced a significant reduction in blood pressure and heart rate in SHR, which was significantly attenuated by the intraperitoneal administration of luzindole, a non-selective melatonin receptor (MT1/MT2) antagonist. Serum melatonin levels in the SHR group were significantly lower than those in the WKY group at 8:00–9:00 and 21:00–22:00, while exercise training reduced this difference. Endothelium-dependent vessel relaxation induced by acetylcholine was significantly blunted in SHR compared with age-matched WKY. Both exercise training and luzindole ameliorated this endothelium-dependent impairment of relaxation in hypertension. Immunohistochemistry and Western blotting showed that the protein expression of the MT2 receptor and eNOS, as well as their colocalization in the endothelial cell layer in SHRs, was significantly decreased; as exercise training suppressed this reduction. These results provide evidence that regular exercise has a beneficial effect on improving endothelium-dependent vasorelaxation in MAs, in which melatonin plays a critical role by acting on MT2 receptors to increase NO production and/or NO bioavailability.

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References

  1. 1.

    Saarela S, Reiter RJ. Function of melatonin in thermoregulatory processes. Life Sci. 1994;54:295–311.

  2. 2.

    Girouard H, Chulak C, Lejossec M, Lamontagne D, De Champlain J. Vasorelaxant effects of the chronic treatment with melatonin on mesenteric artery and aorta of spontaneously hypertensive rats. J Hypertens. 2001;19:1369–77.

  3. 3.

    Kawashima K, Miwa Y, Fujimoto K, Oohata H, Nishino H, Koike H. Antihypertensive action of melatonin in the spontaneously hypertensive rats. Clin Exp Hypertens. 1987;9:1121–31.

  4. 4.

    Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15:434–43.

  5. 5.

    Baltatu OC, Amaral FG, Campos LA, Cipollao-Neto J. Melatonin, mitochondria and hypertension. Cell Mol Life Sci. 2017. https://doi.org/10.1007/s00018-017-2613-y.

  6. 6.

    Jonas M, Garfinkel D, Zisapel N, Laudon M, Grossman E. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press. 2003;12:19–24.

  7. 7.

    Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet. 1995;345:1408.

  8. 8.

    Dwaich KH, Al-Amran FG, Al-Sheibani BI, Al-Aubaidy HA. Melatonin effects on myocardial ischemia-reperfusion injury: Impact on the outcome in patients undergoing coronary artery bypass grafting surgery. Int J Cardiol. 2016;221:977–86.

  9. 9.

    Ekeløf SV, Halladin NL, Jensen SE, Zaremba T, Aarøe J, Kjærgaard B, Simonsen CW, Rosenberg H, Gögenur I. Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction. Heart Vessels. 2016;31:88–95.

  10. 10.

    Girotti L, Lago M, Ianovsky O, Elizari MV, Dini A, Lloret SP, Albornoz LE, Cardinali DP. Low urinary 6-sulfatoxymelatonin levels in patients with severe congestive heart failure. Endocrine. 2003;22:245–8.

  11. 11.

    Dominguez-Rodriguez A, Abreu-Gonzalez P. Future strategies for acute cardioprotection: ‘melatonin as promising therapy’. Cardiovasc Res. 2017;113:1418.

  12. 12.

    Scheer F, Van Montfrans GA, Van Someren EJW, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43:192–7.

  13. 13.

    Zanaboni A, Zanaboni-Muciaccia W. Experimental hypertension in pinealectomised rats. Life Sci. 1967;6:2327–31.

  14. 14.

    Harlow HJ. Influence of the pineal gland and melatonin on blood flow and evaporative water loss during heat stress in rats. J Pineal Res. 1987;4:147–59.

  15. 15.

    Das R, Balonan L, Ballard HJ, Ho S. Chronic hypoxia inhibits the antihypertensive effect of melatonin on pulmonary artery. Int J Cardiol. 2008;126:340–5.

  16. 16.

    Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI. Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci. 2003;8:d1093–108.

  17. 17.

    Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85:335–53.

  18. 18.

    Monroe KK, Watts SW. The vascular reactivity of melatonin. Gen Pharmacol. 1998;30:31–5.

  19. 19.

    Doolen S, Krause DN, Dubocovich ML, Duckles SP. Melatonin mediates two distinct responses in vascular smooth muscle. Eur J Pharmacol. 1998;345:67–9.

  20. 20.

    Evans BK, Mason R, Wilson VG. Evidence for direct vasoconstrictor activity of melatonin in “pressurized” segments of isolated caudal artery from juvenile rats. Naunyn Schmiedebergs Arch Pharmacol. 1992;346:362–5.

  21. 21.

    Geary GG, Krause DN, Duckles SP. Melatonin directly constricts rat cerebral arteries through modulation of potassium channels. Am J Physiol. 1997;273:H1530–6.

  22. 22.

    Viswanathan M, Scalbert E, Delagrange P, Guardiola-Lemaître B, Saavedra JM. Melatonin receptors mediate contraction of a rat cerebral artery. Neuroreport. 1997;8:3847–9.

  23. 23.

    Satake N, Oe H, Shibata S. Vasorelaxing action of melatonin in rat isolated aorta; possible endothelium dependent relaxation. Gen Pharmacol. 1991;22:1127–33.

  24. 24.

    Weekley LB. Melatonin-induced relaxation of rat aorta: interaction with adrenergic agonists. J Pineal Res. 1991;11:28–34.

  25. 25.

    Cimen B, Uz A, Cetin I, Cimen L, Cetin A. Melatonin supplementation ameliorates energy charge and oxidative stress induced by acute exercise in rat heart tissue. Acta Cardiol Sin. 2017;33:530–8.

  26. 26.

    Ianas O, Olinescu R, Badescu I. Melatonin involvement in oxidative processes. Endocrinologie. 1991;29:147–53.

  27. 27.

    Nichols AJ, Wilson AC, Hiley CR. Effects of sympathectomy with 6-hydroxydopamine on cardiac output and its distribution in the rat. Eur J Pharmacol. 1985;109:263–8.

  28. 28.

    Hagberg JM, Park J-J, Brown MD. The role of exercise training in the treatment of hypertension. Sports Med. 2000;30:193–206.

  29. 29.

    de Sousa EC, Abrahin O, Ferreira ALL, Rodrigues RP, Alves EAC, Vieira RP. Resistance training alone reduces systolic and diastolic blood pressure in prehypertensive and hypertensive individuals: meta-analysis. Hypertens Res. 2017;40:927–31.

  30. 30.

    Inder JD, Carlson DJ, Dieberg G, McFarlane JR, Hess NC, Smart NA. Isometric exercise training for blood pressure management: a systematic review and meta-analysis to optimize benefit. Hypertens Res. 2016;39:88–94.

  31. 31.

    Shi L, Zhang H, Chen Y, Liu Y, Lu N, Zhao T, Zhang L. Chronic exercise normalizes changes of Cav1.2 and KCa1.1 channels in mesenteric arteries from spontaneously hypertensive rats. Br J Pharmacol. 2015;172:1846–58.

  32. 32.

    Goessler K, Polito M, Cornelissen VA. Effect of exercise training on the renin-angiotensin-aldosterone system in healthy individuals: a systematic review and meta-analysis. Hypertens Res. 2016;39:119–26.

  33. 33.

    Buxton OM, L’hermite-Baleriaux M, Hirschfeld U, Cauter E. Acute and delayed effects of exercise on human melatonin secretion. J Biol Rhythms. 1997;12:568–74.

  34. 34.

    Escames G, Ozturk G, Baño-Otálora B, Pozo MJ, Madrid JA, Reiter RJ, Serrano E, Concepción M, Acuña-Castroviejo D. Exercise and melatonin in humans: reciprocal benefits. J Pineal Res. 2012;52:1–11.

  35. 35.

    Skrinar GS, Bullen BA, Reppert SM, Peachey SE, Turnbull BA, McArthur JW. Melatonin response to exercise training in women. J Pineal Res. 1989;7:185–94.

  36. 36.

    Rezzani R, Rodella LF, Bonomini F, Tengattini S, Bianchi R, Reiter RJ. Beneficial effects of melatonin in protecting against cyclosporine A-induced cardiotoxicity are receptor mediated. J Pineal Res. 2006;41:288–95.

  37. 37.

    Roque FR, Briones AM, García-Redondo AB, Galán M, Martínez-Revelles S, Avendaño MS, Cachofeiro V, Fernandes T, Vassallo DV, Oliveira EM, Salaices M. Aerobic exercise reduces oxidative stress and improves vascular changes of small mesenteric and coronary arteries in hypertension. Br J Pharmacol. 2013;168:686–703.

  38. 38.

    Mitchell JA, Bornstein DB, Sui X, Hooker SP, Church TS, Lee CD, Lee DC, Blair SN. The impact of combined health factors on cardiovascular disease mortality. Am Heart J. 2010;160:102–8.

  39. 39.

    da Costa Rebelo RM, Schreckenberg R, Schlüter KD. Adverse cardiac remodelling in spontaneously hypertensive rats: acceleration by high aerobic exercise intensity. J Physiol. 2012;590:5389–400.

  40. 40.

    Chen Y, Zhang H, Zhang Y, Lu N, Zhang L, Shi L. Exercise intensity-dependent reverse and adverse remodeling of Cav1.2 channels in mesenteric arteries from spontaneously hypertensive rats. Hypertens Res. 2015;38:656–65.

  41. 41.

    Sun MW, Qian FL, Wang J, Tao T, Guo J, Wang L, Lu AY, Chen H. Low-Intensity Voluntary running lowers blood pressure with simultaneous improvement in endothelium-dependent vasodilatation and insulin sensitivity in aged spontaneously hypertensive rats. Hypertens Res. 2008;31:543–52.

  42. 42.

    Paulis L, Simko F. Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind. Physiol Res. 2007;56:671–84.

  43. 43.

    Agarwal D, Elks CM, Reed SD, Mariappan N, Majid DS, Francis J. Chronic exercise preserves renal structure and hemodynamics in spontaneously hypertensive rats. Antioxid Redox Signal. 2012;16:139–52.

  44. 44.

    Li H, Witte K, August M, Brausch I, Gödtel-Armbrust U, Habermeier A, Closs EI, Oelze M, Münzel T, Fürstermann T, Förstermann U. Reversal of endothelial nitric oxide synthase uncoupling and up-regulation of endothelial nitric oxide synthase expression lowers blood pressure in hypertensive rats. J Am Coll Cardiol. 2006;47:2536–44.

  45. 45.

    Wu CC, Bohr DF. Role of endothelium in the response to endothelin in hypertension. Hypertension. 1990;16:677–81.

  46. 46.

    Dekleva M, Lazic JS, Arandjelovic A, Mazic S. Beneficial and harmful effects of exercise in hypertensive patients: the role of oxidative stress. Hypertens Res. 2017;40:15–20.

  47. 47.

    Battault S, Singh F, Gayrard S, Zoll J, Reboul C, Meyer G. Endothelial function does not improve with high-intensity continuous exercise training in SHR: implications of eNOS uncoupling. Hypertens Res. 2016;39:70–8.

  48. 48.

    Dubocovich ML, Masana MI, Iacob S, Sauri DM. Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn Schmiedebergs Arch Pharmacol. 1997;355:365–75.

  49. 49.

    Dubocovich ML, Yun K, Al-Ghoul WM, Benloucif S, Masana MI. Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J. 1998;12:1211–20.

  50. 50.

    Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, Krause DN. MT(2) melatonin receptors are present and functional in rat caudal artery. J Pharmacol Exp Ther. 2002;302:1295–302.

  51. 51.

    Reiter RJ. Antioxidant actions of melatonin. Adv Pharmacol. 1997;38:103–17.

  52. 52.

    Wakatsuki A, Okatani Y. Melatonin protects against the free radicalinduced impairment of nitric oxide production in the human umbilical artery. J Pineal Res. 2000;28:172–8.

  53. 53.

    Zhao T, Zhang H, Jin C, Qiu F, Wu Y, Shi L. Melatonin mediates vasodilation through both direct and indirect activation of BKCa channels. J Mol Endocrinol. 2017;59:219–33.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (31771312, 31371201), the Beijing Natural Science Foundation (5172023), the Chinese Universities Scientific Fund (2018GJ010), and the National Institutes of Health Grants R01HL135623 (D.X.), R01HD088039 (D.X.), and R03DA041492 (D.X.).

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Correspondence to Daliao Xiao or Lijun Shi.

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