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Central cardiovascular actions of l-homocysteine microinjected into ventrolateral medullary autonomic areas of the rat

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Abstract

Elevated l-homocysteine concentrations in the plasma and cerebrospinal fluid are related to cardiovascular and neuronal diseases, and could contribute to disease development. However, the central cardiovascular actions of l-homocysteine in two important autonomic regulating areas remain unknown: the rostral ventrolateral medulla (RVLM), including pre-sympathetic neurons, and the caudal ventrolateral medulla (CVLM), including interneurons projecting to pre-sympathetic neurons in the RVLM. Therefore, the aim of the current study was to examine the influence of l-homocysteine microinjected into the RVLM and CVLM areas on changes in arterial blood pressure (ABP) and heart rate (HR) of anesthetized rats, as well as the influence of ionotropic excitatory amino acid (iEAA) receptors on the central actions of l-homocysteine. l-Homocysteine solutions were microinjected into the RVLM and CVLM, which were defined according to pressor and depressor responses to l-glutamate microinjections, respectively. ABP and HR increased in the RVLM and decreased in the CVLM after microinjection with l-homocysteine, similar to l-glutamate, in a dose-dependent manner, suggesting mediation of EAA receptors. Prior microinjection of the N-methyl-d-aspartate (NMDA) iEAA receptor antagonist MK801, but not the non-NMDA receptor antagonist CNQX, abolished the observed responses to l-homocysteine in both the RVLM and CVLM. These results indicate the central cardiovascular actions of l-homocysteine via MK801-sensitive receptors of the medullary autonomic neurons in the rat RVLM and CVLM. It remains unknown if the central cardiovascular actions are related to cardiovascular diseases after endogenously and locally augmented l-homocysteine production by disordered metabolism. Further studies on functional significance of l-homocysteine may provide some clue to understand its toxic mechanism.

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Abbreviations

ABP:

Arterial blood pressure

CNQX:

6-Cyano-7-nitroquinoxaline-2, 3-dione

CVLM:

Caudal ventrolateral medulla

HR:

Heart rate

NMDA:

N-methyl-d-aspartate

RVLM:

Rostral ventrolateral medulla

References

  • Aberger K, Chitravanshi VC, Sapru HN (2001) Cardiovascular responses to microinjections of nicotine into the caudal ventrolateral medulla of the rat. Brain Res 892:138–146

    Article  CAS  PubMed  Google Scholar 

  • Abushik PA, Niittykoski M, Giniatullina R, Shakirzyanova A, Bart G, Fayuk D, Sibarov DA, Antonov SM, Giniatullin R (2014) The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells. J Neurochem 129:264–274

    Article  CAS  PubMed  Google Scholar 

  • Blom HJ, Smulders Y (2011) Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 34:75–81

    Article  CAS  PubMed  Google Scholar 

  • Briggs CA, McKenna DG (1996) Effect of MK801 at the human α7 nicotinic acetylcholine receptor. Neuropharmacology 35:407–414

    Article  CAS  PubMed  Google Scholar 

  • Cheng X (2013) Updating the relationship between hyperhomocysteinemia lowering therapy and cardiovascular events. Cardiovasc Ther 31:e19–e26

    Article  CAS  PubMed  Google Scholar 

  • Clarke PBS, Reuben M (1995) Inhibition by dizocilpine (MK801) of striatal dopamine released by MPTP and MPP+: possible action at the dopamine transporter. Br J Pharmacol 114:315–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dampney RAL (1994) Functional organization of central pathways regulating the cardiovascular system. Physiol Rev 74:323–364

    CAS  PubMed  Google Scholar 

  • Galligan JJ, North RA (1990) MK801 blocks nicotinic depolarizations of guinea pig myenteric neurons. Neurosci Lett 108:105–109

    Article  CAS  PubMed  Google Scholar 

  • Grange E, Gharib A, Lepetit P, Guillaud J, Sarda N, Bobillier P (1992) Brain protein synthesis in the conscious rat using l-[35S] methionine: relationship of methionine specific activity between plasma and precursor compartment and evaluation of methionine metabolic pathways. J Neurochem 59:1437–1443

    Article  CAS  PubMed  Google Scholar 

  • Guyenet PG (2006) The sympathetic control of blood pressure. Nat Rev Neurosci 7:335–346

    Article  CAS  PubMed  Google Scholar 

  • Isobe C, Terayama Y (2010) A remarkable increase in total homocysteine concentrations in the CSF of migraine patients with aura. Headache 50:1561–1569

    Article  PubMed  Google Scholar 

  • Lipton SA, Kim W-K, Choi Y-B, Kumar S, D’Emilia DM, Rayudu PV, Arnelle DR, Stamler JS (1997) Neurotoxicity associated with dual actions of homocysteine at the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 94:5923–5928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McBean GJ (2007) Sulfur-containing amino acids. In: Oja SS, Schousboe A, Sransaari P, Abel L (eds) Handbook of neurochemistry and molecular neurobiology: amino acids and peptides in the nervous system, 3rd edn. Springer, US, pp 133–154

    Chapter  Google Scholar 

  • Mendes RH, Mostarda C, Candido GO, Moraes-Silva IC, D’Almeida V, Bello-Klein A, Irigoyen MC, Rigatto K (2014) Moderate hyperhomocysteinemia provokes dysfunction of cardiovascular autonomic system and liver oxidative stress in rats. Auton Neurosci 180:43–47

    Article  CAS  PubMed  Google Scholar 

  • Muntzel MS, Joseph T, Onwumere O (2006) Acute homocysteine administration does not elevate sympathetic nerve activity in rats. Atherosclerosis 184:290–294

    Article  CAS  PubMed  Google Scholar 

  • O’Connor E, Devesa A, Garcia C, Puertes IR, Pellin A, Viña JR (1995) Biosynthesis and maintenance of GSH in primary astrocyte cultures: role of cysteine and ascorbate. Brain Res 680:157–163

    Article  PubMed  Google Scholar 

  • Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580:2994–3005

    Article  CAS  PubMed  Google Scholar 

  • Resstel LBM, de Andrade CR, Haddad R, Eberlin MN, de Oliveira AM, Correa FMA (2008) Hyperhomocysteinaemia-induced cardiovascular changes in rats. Clin Exp Pharmacol Physiol 35:949–956

    Article  CAS  PubMed  Google Scholar 

  • Schreihofer AM, Sved AF (2011) The ventrolateral medulla and sympathetic regulation of arterial pressure. In: Llewellyn-Smith IJ, Verberne AJM (eds) Central regulation of autonomic functions, 2nd edn. Oxford University Press, New York, pp 78–97

    Chapter  Google Scholar 

  • Stipanuk MH, Ueki I (2011) Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. J Inherit Metab Dis 34:17–32

    Article  CAS  PubMed  Google Scholar 

  • Takemoto Y (2004) l-Proline microinjected into the rat ventrolateral medulla induces a depressor response distinct from l-glutamate. Jpn J Physiol 54:339–345

    Article  CAS  PubMed  Google Scholar 

  • Takemoto Y (2005) Depressor responses to l-proline microinjected into the rat ventrolateral medulla are mediated by ionotropic excitatory amino acid receptors. Auton Neurosci 120:108–112

    Article  CAS  PubMed  Google Scholar 

  • Takemoto Y (2007) The mapped pattern of kainate on blood pressure responses is similar to that of l-proline in the ventrolateral medulla of the rat. Neurosci Lett 425:12–17

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Takemoto Y (2013) Pressor response to l-cysteine injected into the cisterna magna of conscious rats involves recruitment of hypothalamic vasopressinergic neurons. Amino Acids 44:1053–1060

    Article  CAS  PubMed  Google Scholar 

  • Takemoto Y (2014a) Functional cardiovascular action of l-cysteine microinjected into pressor sites of the rostral ventrolateral medulla of the rat. Amino Acids 46:863–872

    Article  CAS  PubMed  Google Scholar 

  • Takemoto Y (2014b) l-Cysteine and l-AP4 microinjections in the rat caudal ventrolateral medulla decrease arterial blood pressure. Auton Neurosci 186:45–53

    Article  CAS  PubMed  Google Scholar 

  • Troen AM (2005) The central nervous system in animal models of hyperhomocysteinemia. Prog Neuro-Psychopharm Biol Psychiatry 29:1140–1151

    Article  CAS  Google Scholar 

  • Tseng CJ, Appalsamy M, Robertson D, Mosqueda-Garcia R (1993) Effects of nicotine on brain stem mechanisms of cardiovascular control. J Pharmacol Exp Ther 265:1511–1518

    CAS  PubMed  Google Scholar 

  • Tsuchihashi T, Averill DB (1993) Metabotropic glutamate receptors in the ventrolateral medulla of rats. Hypertension 21:739–744

    Article  CAS  PubMed  Google Scholar 

  • Tsuchihashi T, Liu Y, Kagiyama S, Matsumura K, Abe I, Fujishima M (2000) Metabotropic glutamate receptor subtypes involved in cardiovascular regulation in the rostral ventrolateral medulla of rats. Brain Res Bull 52:279–283

    Article  CAS  PubMed  Google Scholar 

  • van Guldener C, Nanayakkara PWB, Stehouwer CDA (2003) Homocysteine and blood pressure. Curr Hypertens Rep 5:26–31

    Article  PubMed  Google Scholar 

  • Yeganeh F, Nikbakht F, Bahmanpour S, Rastergar K, Namavar R (2013) Neuroprotective effects of NMDA and group I metabotropic glutamate receptor antagonists against neurodegeneration induced by homocysteine in rat hippocampus: in vivo study. J Mol Neurosci 50:551–557

    Article  CAS  PubMed  Google Scholar 

  • Yue J-L, Goshima Y, Miyamae T, Misu Y (1993a) Evidence for l-DOPA relevant to modulation of sympathetic activity in the rostral ventrolateral medulla of rats. Brain Res 629:310–314

    Article  CAS  PubMed  Google Scholar 

  • Yue J-L, Goshima Y, Misu Y (1993b) Transmitter-like l-3,4-dihydroxyphenylalanine tonically functions to mediated vasodepressor control in the caudal ventrolateral medulla of rats. Neurosci Lett 159:103–106

    Article  CAS  PubMed  Google Scholar 

  • Zieminska E, Lazarewicz JW (2006) Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studied in vivo: the role of NMDA and group I metabotropic glutamate receptors. Acta Neurobiol Exp 66:301–309

    Google Scholar 

  • Zieminska E, Stafiej A, Lazarevicz JW (2003) Role of group I metabotropic glutamate receptors and NMDA receptors in homocysteine-evoked acute neurodegeneration of cultured cerebellar granule neurons. Neurochem Int 43:481–492

    Article  CAS  PubMed  Google Scholar 

  • Zoccolella S, Bendotti C, Beghi E, Logroscino G (2010) Homocysteine levels and amyotrophic lateral sclerosis: a possible link. Amyotroph Lateral Scler 11:140–147

    Article  CAS  PubMed  Google Scholar 

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  1. Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8551, Japan

    Yumi Takemoto

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  1. Yumi Takemoto
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Correspondence to Yumi Takemoto.

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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.

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Handling Editor: H. Jakubowski.

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Takemoto, Y. Central cardiovascular actions of l-homocysteine microinjected into ventrolateral medullary autonomic areas of the rat. Amino Acids 48, 2215–2225 (2016). https://doi.org/10.1007/s00726-016-2259-3

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  • DOI: https://doi.org/10.1007/s00726-016-2259-3

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