Amino Acids

, Volume 48, Issue 7, pp 1581–1590 | Cite as

Hypotensive effect of S-adenosyl-l-methionine in hypertensive rats is reduced by autonomic ganglia and KATP channel blockers

  • Mariusz SikoraEmail author
  • Kinga Pham
  • Marcin Ufnal
Original Article


S-adenosyl-l-methionine (SAM) is an amino acid involved in a number of physiological processes in the nervous system. Some evidence suggests a therapeutic potential of SAM in hypertension. In this study we investigated the effect of intracerebroventricular (ICV) infusions of SAM on arterial blood pressure in rats. Mean arterial blood pressure (MABP) and heart rate (HR) were measured at baseline and during ICV infusion of either SAM or vehicle (aCSF; controls) in conscious, male normotensive Wistar Kyoto rats (WKY) and Spontaneously Hypertensive Rats (SHR). MABP and HR were not affected by the vehicle. WKY rats infused with SAM (10 μM, 100 μM and 1 mM) showed a biphasic hemodynamic response i.e., mild hypotension and bradycardia followed by a significant increase in MABP and HR. On the contrary, SHR infused with SAM showed a dose-dependent hypotensive response. In separate series of experiments, pretreatment with hexamethonium, a ganglionic blocker as well as pretreatment with glibenclamide, a KATP channel blocker reduced the hemodynamic effects of SAM. SAM may affect the nervous control of arterial blood pressure via the autonomic nervous system and KATP channel-dependent mechanisms.


Blood pressure Brain Hypertension S-adenosyl-l-methionine 



This study was funded by the National Science Center Grant No. 2011/01/N/NZ4/03682 and Medical University of Warsaw.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

This article does not contain any studies with human participants performed by any of the authors.


  1. Ashcroft FM, Gribble FM (1998) Correlating structure and function in ATP-sensitive K+ channels. Trends Neurosci 21(7):288–294CrossRefPubMedGoogle Scholar
  2. Asor E, Stempler S, Avital A, Klein E, Ruppin E, Ben-Shachar D (2015) The role of branched chain amino acid and tryptophan metabolism in rat’s behavioral diversity: Intertwined peripheral and brain effects. Eur Neuropsychopharmacol 25(10):1695–1705. doi: 10.1016/j.euroneuro.2015.07.009 CrossRefPubMedGoogle Scholar
  3. Bencze M, Behuliak M, Zicha J (2013) The impact of four different classes of anesthetics on the mechanisms of blood pressure regulation in normotensive and spontaneously hypertensive rats. Physiol Res 62(5):471–478PubMedGoogle Scholar
  4. Bottiglieri T (2002) S-Adenosyl-l-methionine (SAMe): from the bench to the bedside–molecular basis of a pleiotrophic molecule. Am J Clin Nutr 76(5):1151S–1157SPubMedGoogle Scholar
  5. Brown MD, Dudeja PK, Brasitus TA (1988) S-adenosyl-l-methionine modulates Na+ + K+ -ATPase activity in rat colonic basolateral membranes. Biochem J 251(1):215–222CrossRefPubMedPubMedCentralGoogle Scholar
  6. De Berardis D, Orsolini L, Serroni N, Girinelli G, Iasevoli F, Tomasetti C, de Bartolomeis A, Mazza M, Valchera A, Fornaro M, Perna G, Piersanti M, Di Nicola M, Cavuto M, Martinotti G, Di Giannantonio M (2016) A comprehensive review on the efficacy of S-Adenosyl-l-methionine in Major Depressive Disorder. CNS Neurol Disord Drug Targets 15(1):35–44CrossRefPubMedGoogle Scholar
  7. Ding YA, Chang ST, Shieh SM, Huang WC (1988) Antihypertensive and renal effects of cilazapril and their reversal by angiotensin in renovascular hypertensive rats. Clin Sci (Lond) 74(4):365–372CrossRefGoogle Scholar
  8. Duan XC, Guo R, Liu SY, Xiao L, Xue HM, Guo Q, Jin S, Wu YM (2015) Gene transfer of cystathionine beta-synthase into RVLM increases hydrogen sulfide-mediated suppression of sympathetic outflow via KATP channel in normotensive rats. Am J Physiol Heart Circ Physiol 308(6):H603–H611. doi: 10.1152/ajpheart.00693.2014 CrossRefPubMedGoogle Scholar
  9. Eto K, Kimura H (2002) A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase. J Biol Chem 277(45):42680–42685. doi: 10.1074/jbc.M205835200 CrossRefPubMedGoogle Scholar
  10. Fan Y, Lan L, Zheng L, Ji X, Lin J, Zeng J, Huang R, Sun J (2015) Spontaneous white matter lesion in brain of stroke-prone renovascular hypertensive rats: a study from MRI, pathology and behavior. Metab Brain Dis 30(6):1479–1486. doi: 10.1007/s11011-015-9722-9 CrossRefPubMedGoogle Scholar
  11. Furujo M, Kinoshita M, Nagao M, Kubo T (2012) Methionine adenosyltransferase I/III deficiency: neurological manifestations and relevance of S-adenosylmethionine. Mol Genet Metab 107(3):253–256. doi: 10.1016/j.ymgme.2012.08.002 CrossRefPubMedGoogle Scholar
  12. Grillo MA, Colombatto S (2008) S-adenosylmethionine and its products. Amino Acids 34(2):187–193. doi: 10.1007/s00726-007-0500-9 CrossRefPubMedGoogle Scholar
  13. Guo Q, Jin S, Wang XL, Wang R, Xiao L, He RR, Wu YM (2011) Hydrogen sulfide in the rostral ventrolateral medulla inhibits sympathetic vasomotor tone through ATP-sensitive K+ channels. J Pharmacol Exp Ther 338(2):458–465. doi: 10.1124/jpet.111.180711 CrossRefPubMedGoogle Scholar
  14. Hawkins RA, O’Kane RL, Simpson IA, Vina JR (2006) Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 136(1 Suppl):218S–226SPubMedGoogle Scholar
  15. Jordi J, Herzog B, Camargo SM, Boyle CN, Lutz TA, Verrey F (2013) Specific amino acids inhibit food intake via the area postrema or vagal afferents. J Physiol 591(Pt 22):5611–5621. doi: 10.1113/jphysiol.2013.258947 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kamoun P (2004) Endogenous production of hydrogen sulfide in mammals. Amino Acids 26(3):243–254. doi: 10.1007/s00726-004-0072-x CrossRefPubMedGoogle Scholar
  17. Kampfer AJ, Balog EM (2010) S-adenosyl-l-methionine regulation of the cardiac ryanodine receptor involves multiple mechanisms. Biochemistry 49(35):7600–7614. doi: 10.1021/bi100599b CrossRefPubMedGoogle Scholar
  18. Laffin LJ, Bakris GL (2015) Hypertension and new treatment approaches targeting the sympathetic nervous system. Curr Opin Pharmacol 21:20–24. doi: 10.1016/j.coph.2014.12.006 CrossRefPubMedGoogle Scholar
  19. Lake KD, Martin BR, Kunos G, Varga K (1997) Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 29(5):1204–1210CrossRefPubMedGoogle Scholar
  20. Lakhi S, Snow W, Fry M (2013) Insulin modulates the electrical activity of subfornical organ neurons. Neuroreport 24(6):329–334. doi: 10.1097/WNR.0b013e32835ffc14 CrossRefPubMedGoogle Scholar
  21. Li DP, Chen SR, Pan HL (2010) Adenosine inhibits paraventricular pre-sympathetic neurons through ATP-dependent potassium channels. J Neurochem 113(2):530–542. doi: 10.1111/j.1471-4159.2010.06618.x CrossRefPubMedGoogle Scholar
  22. Liu WQ, Chai C, Li XY, Yuan WJ, Wang WZ, Lu Y (2011) The cardiovascular effects of central hydrogen sulfide are related to K(ATP) channels activation. Physiol Res 60(5):729–738PubMedGoogle Scholar
  23. Losada ME, Rubio MC (1989) Acute effects of S-adenosyl-l-methionine on catecholaminergic central function. Eur J Pharmacol 163(2–3):353–356CrossRefPubMedGoogle Scholar
  24. Lu SC, Mato JM (2012) S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92(4):1515–1542. doi: 10.1152/physrev.00047.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Montgomery SE, Sepehry AA, Wangsgaard JD, Koenig JE (2014) The effect of S-adenosylmethionine on cognitive performance in mice: an animal model meta-analysis. PLoS One 9(10):e107756. doi: 10.1371/journal.pone.0107756 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Otero-Losada ME, Rubio MC (1989) Acute changes in 5-HT metabolism after S-adenosyl-l-methionine administration. Gen Pharmacol 20(4):403–406CrossRefPubMedGoogle Scholar
  27. Panza F, Frisardi V, Capurso C, D’Introno A, Colacicco AM, Di Palo A, Imbimbo BP, Vendemiale G, Capurso A, Solfrizzi V (2009) Polyunsaturated fatty acid and S-adenosylmethionine supplementation in predementia syndromes and Alzheimer’s disease: a review. Sci World J 9:373–389. doi: 10.1100/tsw.2009.48 CrossRefGoogle Scholar
  28. Qiao W, Yang L, Li XY, Cao N, Wang WZ, Chai C, Lu Y (2011) The cardiovascular inhibition functions of hydrogen sulfide within the nucleus tractus solitarii are mediated by the activation of KATP channels and glutamate receptors mechanisms. Pharmazie 66(4):287–292PubMedGoogle Scholar
  29. Roy A, Khan AH, Islam MT, Prieto MC, Majid DS (2012) Interdependency of cystathione gamma-lyase and cystathione beta-synthase in hydrogen sulfide-induced blood pressure regulation in rats. Am J Hypertens 25(1):74–81. doi: 10.1038/ajh.2011.149 CrossRefPubMedGoogle Scholar
  30. Sarris J, Papakostas GI, Vitolo O, Fava M, Mischoulon D (2014) S-Adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. J Affect Disord 164:76–81. doi: 10.1016/j.jad.2014.03.041 CrossRefPubMedGoogle Scholar
  31. Sikora M, Drapala A, Ufnal M (2014) Exogenous hydrogen sulfide causes different hemodynamic effects in normotensive and hypertensive rats via neurogenic mechanisms. Pharmacol Rep 66(5):751–758. doi: 10.1016/j.pharep.2014.04.004 CrossRefPubMedGoogle Scholar
  32. Stark R, Reichenbach A, Andrews ZB (2015) Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis. Mol Cell Endocrinol 418(Pt 1):9–16. doi: 10.1016/j.mce.2015.08.002 CrossRefPubMedGoogle Scholar
  33. Szczepanska-Sadowska E (2006) Neuropeptides in neurogenic disorders of the cardiovascular control. J Physiol Pharmacol 57(Suppl 11):31–53PubMedGoogle Scholar
  34. Szczepanska-Sadowska E, Cudnoch-Jedrzejewska A, Ufnal M, Zera T (2010) Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases. J Physiol Pharmacol 61(5):509–521PubMedGoogle Scholar
  35. Takemoto Y (1990) Amino acids with central pressor effect in conscious rats. Jpn J Physiol 40(4):561–565CrossRefPubMedGoogle Scholar
  36. Takemoto Y (1991) Central depressor effects of amino acids in conscious normotensive and two-kidney, one-clip renovascular hypertensive rats. Jpn J Physiol 41(5):717–724CrossRefPubMedGoogle Scholar
  37. Takemoto Y (2012) Amino acids that centrally influence blood pressure and regional blood flow in conscious rats. J Amino Acids 2012:831759. doi: 10.1155/2012/831759 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Takemoto Y (2013) Pressor response to l-cysteine injected into the cisterna magna of conscious rats involves recruitment of hypothalamic vasopressinergic neurons. Amino Acids 44(3):1053–1060. doi: 10.1007/s00726-012-1440-6 CrossRefPubMedGoogle Scholar
  39. Takemoto Y (2014a) Cardiovascular actions of l-cysteine and l-cysteine sulfinic acid in the nucleus tractus solitarius of the rat. Amino Acids 46(7):1707–1713. doi: 10.1007/s00726-014-1733-z CrossRefPubMedGoogle Scholar
  40. Takemoto Y (2014b) Functional cardiovascular action of l-cysteine microinjected into pressor sites of the rostral ventrolateral medulla of the rat. Amino Acids 46(4):863–872. doi: 10.1007/s00726-013-1651-5 CrossRefPubMedGoogle Scholar
  41. Takemoto Y (2014c) l-Cysteine and L-AP4 microinjections in the rat caudal ventrolateral medulla decrease arterial blood pressure. Auton Neurosci 186:45–53. doi: 10.1016/j.autneu.2014.09.018 CrossRefPubMedGoogle Scholar
  42. Toal CB, Leenen FH (1985) Blood pressure responsiveness during the development of hypertension in the conscious spontaneously hypertensive rat. Can J Physiol Pharmacol 63(10):1258–1262CrossRefPubMedGoogle Scholar
  43. Ufnal M, Sikora M (2011) The role of brain gaseous transmitters in the regulation of the circulatory system. Curr Pharm Biotechnol 12(9):1322–1333CrossRefPubMedGoogle Scholar
  44. Ufnal M, Skrzypecki J (2014) Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs. Neuropeptides 48(2):65–73. doi: 10.1016/j.npep.2014.01.003 CrossRefPubMedGoogle Scholar
  45. Ufnal M, Sikora M, Dudek M (2008) Exogenous hydrogen sulfide produces hemodynamic effects by triggering central neuroregulatory mechanisms. Acta Neurobiol Exp (Wars) 68(3):382–388Google Scholar
  46. Vina JR, Davis DW, Hawkins RA (1986) The influence of nitrous oxide on methionine, S-adenosylmethionine, and other amino acids. Anesthesiology 64(4):490–495CrossRefPubMedGoogle Scholar
  47. Wang R (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92(2):791–896. doi: 10.1152/physrev.00017.2011 CrossRefPubMedGoogle Scholar
  48. Yan J, Li L, Khatibi NH, Yang L, Wang K, Zhang W, Martin RD, Han J, Zhang J, Zhou C (2011) Blood-brain barrier disruption following subarchnoid hemorrhage may be faciliated through PUMA induction of endothelial cell apoptosis from the endoplasmic reticulum. Exp Neurol 230(2):240–247. doi: 10.1016/j.expneurol.2011.04.022 CrossRefPubMedGoogle Scholar
  49. Yang Y, Rosenberg GA (2011) Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke 42(11):3323–3328. doi: 10.1161/STROKEAHA.110.608257 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Yang HT, Chien YW, Tsen JH, Chang CC, Chang JH, Huang SY (2009) Taurine supplementation improves the utilization of sulfur-containing amino acids in rats continually administrated alcohol. J Nutr Biochem 20(2):132–139. doi: 10.1016/j.jnutbio.2008.01.009 CrossRefPubMedGoogle Scholar
  51. Young SN, Shalchi M (2005) The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain. J Psychiatry Neurosci 30(1):44–48PubMedPubMedCentralGoogle Scholar
  52. Zhang Y, Wang H, Sun HW, Chen YL, Ouyang JY, Wang Y, Wang L, Zhang XY (2014) Correlation between cystathionine beta-synthase T883C genetic polymorphism and primary hypertension. Exp Ther Med 8(3):713–718. doi: 10.3892/etm.2014.1799 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  1. 1.Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical ResearchThe Medical University of WarsawWarsawPoland

Personalised recommendations