Neuroscience Bulletin

, Volume 35, Issue 1, pp 124–132 | Cite as

Impaired Hypothalamic Regulation of Sympathetic Outflow in Primary Hypertension

  • Jing-Jing Zhou
  • Hui-Jie Ma
  • Jian-Ying Shao
  • Hui-Lin Pan
  • De-Pei LiEmail author


The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.


Hypothalamus Paraventricular nucleus Synaptic plasticity Essential hypertension Sympathetic nervous system 



The studies conducted in the authors’ laboratories were supported by National Institutes of Health Grants HL131161, HL139523, and HL142133.


  1. 1.
    Gao Y, Zhou JJ, Zhu Y, Kosten T, Li DP. Chronic unpredictable mild stress induces loss of GABA inhibition in corticotrophin-releasing hormone-expressing neurons through NKCC1 upregulation. Neuroendocrinology 2017, 104: 194–208.Google Scholar
  2. 2.
    Zhou JJ, Gao Y, Zhang X, Kosten TA, Li DP. Enhanced hypothalamic NMDA receptor activity contributes to hyperactivity of HPA axis in chronic stress in male rats. Endocrinology 2018, 159: 1537–1546.Google Scholar
  3. 3.
    Saper CB, Loewy AD, Swanson LW, Cowan WM. Direct hypothalamo-autonomic connections. Brain Res 1976, 117: 305–312.Google Scholar
  4. 4.
    Shafton AD, Ryan A, Badoer E. Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Brain Res 1998, 801: 239–243.Google Scholar
  5. 5.
    Affleck VS, Coote JH, Pyner S. The projection and synaptic organisation of NTS afferent connections with presympathetic neurons, GABA and nNOS neurons in the paraventricular nucleus of the hypothalamus. Neuroscience 2012, 219: 48–61.Google Scholar
  6. 6.
    Qi J, Zhang DM, Suo YP, Song XA, Yu XJ, Elks C, et al. Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovasc Toxicol 2013, 13: 48–54.Google Scholar
  7. 7.
    Bardgett ME, Holbein WW, Herrera-Rosales M, Toney GM. Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-alpha. Hypertension 2014, 63: 527–534.Google Scholar
  8. 8.
    Cardinale JP, Sriramula S, Mariappan N, Agarwal D, Francis J. Angiotensin II-induced hypertension is modulated by nuclear factor-kappaBin the paraventricular nucleus. Hypertension 2012, 59: 113–121.Google Scholar
  9. 9.
    Sriramula S, Xia H, Xu P, Lazartigues E. Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation. Hypertension 2015, 65: 577–586.Google Scholar
  10. 10.
    Yu Y, Xue BJ, Zhang ZH, Wei SG, Beltz TG, Guo F, et al. Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension. Hypertension 2013, 61: 842–849.Google Scholar
  11. 11.
    Su Q, Qin DN, Wang FX, Ren J, Li HB, Zhang M, et al. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicol Appl Pharmacol 2014, 276: 115–120.Google Scholar
  12. 12.
    Yuan N, Zhang F, Zhang LL, Gao J, Zhou YB, Han Y, et al. SOD1 gene transfer into paraventricular nucleus attenuates hypertension and sympathetic activity in spontaneously hypertensive rats. Pflugers Arch 2013, 465: 261–270.Google Scholar
  13. 13.
    Zhou JJ, Yuan F, Zhang Y, Li DP. Upregulation of orexin receptor in paraventricular nucleus promotes sympathetic outflow in obese Zucker rats. Neuropharmacology 2015, 99: 481–490.Google Scholar
  14. 14.
    Larson RA, Gui L, Huber MJ, Chapp AD, Zhu J, LaGrange LP, et al. Sympathoexcitation in ANG II-salt hypertension involves reduced SK channel function in the hypothalamic paraventricular nucleus. Am J Physiol Heart Circ Physiol 2015, 308: H1547–1555.Google Scholar
  15. 15.
    Sawchenko PE, Swanson LW. Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses. Science 1981, 214: 685–687.Google Scholar
  16. 16.
    Palkovits M, Mezey E, Zaborszky L, Feminger A, Versteeg DH, Wijnen HJ, et al. Adrenergic innervation of the rat hypothalamus. Neurosci Lett 1980, 18: 237–243.Google Scholar
  17. 17.
    Sawchenko PE, Swanson LW. The organization of noradrenergic pathways from the brainstem to the paraventricular and supraoptic nuclei in the rat. Brain Res 1982, 257: 275–325.Google Scholar
  18. 18.
    Marcilhac A, Siaud P. Identification of projections from the central nucleus of the amygdala to the paraventricular nucleus of the hypothalamus which are immunoreactive for corticotrophin-releasing hormone in the rat. Exp Physiol 1997, 82: 273–281.Google Scholar
  19. 19.
    Lin L, York DA. Amygdala enterostatin induces c-Fos expression in regions of hypothalamus that innervate the PVN. Brain Res 2004, 1020: 147–153.Google Scholar
  20. 20.
    Llewellyn T, Zheng H, Liu X, Xu B, Patel KP. Median preoptic nucleus and subfornical organ drive renal sympathetic nerve activity via a glutamatergic mechanism within the paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 2012, 302: 424–432.Google Scholar
  21. 21.
    Hubschle T, McKinley MJ, Oldfield BJ. Efferent connections of the lamina terminalis, the preoptic area and the insular cortex to submandibular and sublingual gland of the rat traced with pseudorabies virus. Brain Res 1998, 806: 219–231.Google Scholar
  22. 22.
    Sawchenko PE, Swanson LW. The organization of forebrain afferents to the paraventricular and supraoptic nuclei of the rat. J Comp Neurol 1983, 218: 121–144.Google Scholar
  23. 23.
    Clement DL, Pelletier CL, Shepherd JT. Role of vagal afferents in the control of renal sympathetic nerve activity in the rabbit. Circ Res 1972, 31: 824–830.Google Scholar
  24. 24.
    Karim F, Kidd C, Malpus CM, Penna PE. The effects of stimulation of the left atrial receptors on sympathetic efferent nerve activity. J Physiol 1972, 227: 243–260.Google Scholar
  25. 25.
    Kappagoda CT, Linden RJ, Snow HM. Effect of stimulating right atrial receptors on urine flow in the dog. J Physiol 1973, 235: 493–502.Google Scholar
  26. 26.
    Shi P, Stocker SD, Toney GM. Organum vasculosum laminae terminalis contributes to increased sympathetic nerve activity induced by central hyperosmolality. Am J Physiol Regul Integr Comp Physiol 2007, 293: R2279–2289.Google Scholar
  27. 27.
    Coote JH. A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney. Exp Physiol 2005, 90: 169–173.Google Scholar
  28. 28.
    Schramm LP, Strack AM, Platt KB, Loewy AD. Peripheral and central pathways regulating the kidney: a study using pseudorabies virus. Brain Res 1993, 616: 251–262.Google Scholar
  29. 29.
    Jansen AS, Nguyen XV, Karpitskiy V, Mettenleiter TC, Loewy AD. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science 1995, 270: 644–646.Google Scholar
  30. 30.
    Pyner S, Coote JH. Identification of branching paraventricular neurons of the hypothalamus that project to the rostroventrolateral medulla and spinal cord. Neuroscience 2000, 100: 549–556.Google Scholar
  31. 31.
    Coldren KM, Li DP, Kline DD, Hasser EM, Heesch CM. Acute hypoxia activates neuroendocrine, but not presympathetic, neurons in the paraventricular nucleus of the hypothalamus: differential role of nitric oxide. Am J Physiol Regul Integr Comp Physiol 2017, 312: R982–r995.Google Scholar
  32. 32.
    Hallbeck M, Larhammar D, Blomqvist A. Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord. J Comp Neurol 2001, 433: 222–238.Google Scholar
  33. 33.
    Biag J, Huang Y, Gou L, Hintiryan H, Askarinam A, Hahn JD, et al. Cyto- and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6J male mouse: a study of immunostaining and multiple fluorescent tract tracing. J Comp Neurol 2012, 520: 6–33.Google Scholar
  34. 34.
    Li DP, Yang Q, Pan HM, Pan HL. Plasticity of pre- and postsynaptic GABAB receptor function in the paraventricular nucleus in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2008, 295: H807–815.Google Scholar
  35. 35.
    Li DP, Yang Q, Pan HM, Pan HL. Pre- and postsynaptic plasticity underlying augmented glutamatergic inputs to hypothalamic presympathetic neurons in spontaneously hypertensive rats. J Physiol 2008, 586: 1637–1647.Google Scholar
  36. 36.
    Dutar P, Nicoll RA. A physiological role for GABAB receptors in the central nervous system. Nature 1988, 332: 156–158.Google Scholar
  37. 37.
    Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, et al. (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 1980, 283: 92–94.Google Scholar
  38. 38.
    Ramchandra R, Hood SG, Frithiof R, McKinley MJ, May CN. The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep. J Physiol 2013, 591: 93–107.Google Scholar
  39. 39.
    Li DP, Pan HL. Role of gamma-aminobutyric acid (GABA)A and GABAB receptors in paraventricular nucleus in control of sympathetic vasomotor tone in hypertension. J Pharmacol Exp Ther 2007, 320: 615–626.Google Scholar
  40. 40.
    Akine A, Montanaro M, Allen AM. Hypothalamic paraventricular nucleus inhibition decreases renal sympathetic nerve activity in hypertensive and normotensive rats. Auton Neurosci 2003, 108: 17–21.Google Scholar
  41. 41.
    Zahner MR, Pan HL. Role of paraventricular nucleus in the cardiogenic sympathetic reflex in rats. Am J Physiol Regul Integr Comp Physiol 2005, 288: 420–426.Google Scholar
  42. 42.
    Li DP, Pan HL. Glutamatergic inputs in the hypothalamic paraventricular nucleus maintain sympathetic vasomotor tone in hypertension. Hypertension 2007, 49: 916–925.Google Scholar
  43. 43.
    Okamoto K, Aoki K. Development of a strain of spontaneously hypertensive rats. Jpn Circ J 1963, 27: 282–293.Google Scholar
  44. 44.
    Takeda K, Nakata T, Takesako T, Itoh H, Hirata M, Kawasaki S, et al. Sympathetic inhibition and attenuation of spontaneous hypertension by PVN lesions in rats. Brain Res 1991, 543: 296–300.Google Scholar
  45. 45.
    Li DP, Zhu LH, Pachuau J, Lee HA, Pan HL. mGluR5 Upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci 2014, 34: 4309–4317.Google Scholar
  46. 46.
    Li DP, Pan HL. Plasticity of GABAergic control of hypothalamic presympathetic neurons in hypertension. Am J Physiol Heart Circ Physiol 2006, 290: 1110–1119.Google Scholar
  47. 47.
    Ichida T, Takeda K, Sasaki S, Nakagawa M, Hashimoto T, Kuriyama K. Age-related decrease of gamma-aminobutyric acid (GABA) release in brain of spontaneously hypertensive rats. Life Sci 1996, 58: 209–215.Google Scholar
  48. 48.
    Kunkler PE, Hwang BH. Lower GABAA receptor binding in the amygdala and hypothalamus of spontaneously hypertensive rats. Brain Res Bull 1995, 36: 57–61.Google Scholar
  49. 49.
    Kaila K, Voipio J, Paalasmaa P, Pasternack M, Deisz RA. The role of bicarbonate in GABAA receptor-mediated IPSPs of rat neocortical neurones. J Physiol 1993, 464: 273–289.Google Scholar
  50. 50.
    Payne JA, Rivera C, Voipio J, Kaila K. Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci 2003, 26: 199–206.Google Scholar
  51. 51.
    Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, et al. The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 1999, 397: 251–255.Google Scholar
  52. 52.
    Ye ZY, Li DP, Byun HS, Li L, Pan HL. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. J Neurosci 2012, 32: 8560–8568.Google Scholar
  53. 53.
    Kim YB, Kim YS, Kim WB, Shen FY, Lee SW, Chung HJ, et al. GABAergic excitation of vasopressin neurons: possible mechanism underlying sodium-dependent hypertension. Circ Res 2013, 113: 1296–1307.Google Scholar
  54. 54.
    Li DP, Zhou JJ, Zhang J, Pan HL. CaMKII regulates synaptic NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension. J Neurosci 2017, 37: 10690–10699.Google Scholar
  55. 55.
    Qiao X, Zhou JJ, Li DP, Pan HL. Src kinases regulate glutamatergic input to hypothalamic presympathetic neurons and sympathetic outflow in hypertension. Hypertension 2017, 69: 154–162.Google Scholar
  56. 56.
    Ye ZY, Li L, Li DP, Pan HL. Casein kinase 2-mediated synaptic GluN2A up-regulation increases N-methyl-D-aspartate receptor activity and excitability of hypothalamic neurons in hypertension. J Biol Chem 2012, 287: 17438–17446.Google Scholar
  57. 57.
    Gabor A, Leenen FH. Cardiovascular effects of angiotensin II and glutamate in the PVN of Dahl salt-sensitive rats. Brain Res 2012, 1447: 28–37.Google Scholar
  58. 58.
    Glass MJ, Wang G, Coleman CG, Chan J, Ogorodnik E, Van Kempen TA, et al. NMDA receptor plasticity in the hypothalamic paraventricular nucleus contributes to the elevated blood pressure produced by angiotensin II. J Neurosci 2015, 35: 9558–9567.Google Scholar
  59. 59.
    Biancardi VC, Campos RR, Stern JE. Altered balance of gamma-aminobutyric acidergic and glutamatergic afferent inputs in rostral ventrolateral medulla-projecting neurons in the paraventricular nucleus of the hypothalamus of renovascular hypertensive rats. J Comp Neurol 2010, 518: 567–585.Google Scholar
  60. 60.
    Wang YT, Salter MW. Regulation of NMDA receptors by tyrosine kinases and phosphatases. Nature 1994, 369: 233–235.Google Scholar
  61. 61.
    Lu WY, Xiong ZG, Lei S, Orser BA, Dudek E, Browning MD, et al. G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci 1999, 2: 331–338.Google Scholar
  62. 62.
    Chergui K, Svenningsson P, Greengard P. Physiological role for casein kinase 1 in glutamatergic synaptic transmission. J Neurosci 2005, 25: 6601–6609.Google Scholar
  63. 63.
    Kimura R, Matsuki N. Protein kinase CK2 modulates synaptic plasticity by modification of synaptic NMDA receptors in the hippocampus. J Physiol 2008, 586: 3195–3206.Google Scholar
  64. 64.
    Omkumar RV, Kiely MJ, Rosenstein AJ, Min KT, Kennedy MB. Identification of a phosphorylation site for calcium/calmodulindependent protein kinase II in the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 1996, 271: 31670–31678.Google Scholar
  65. 65.
    Li DP, Zhou JJ, Pan HL. Endogenous casein kinase-1 modulates NMDA receptor activity of hypothalamic presympathetic neurons and sympathetic outflow in hypertension. J Physiol 2015, 593: 4439–4452.Google Scholar
  66. 66.
    Yang M, Leonard JP. Identification of mouse NMDA receptor subunit NR2A C-terminal tyrosine sites phosphorylated by coexpression with v-Src. J Neurochem 2001, 77: 580–588.Google Scholar
  67. 67.
    Chung HJ, Huang YH, Lau LF, Huganir RL. Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand. J Neurosci 2004, 24: 10248–10259.Google Scholar
  68. 68.
    Donella-Deana A, Cesaro L, Sarno S, Ruzzene M, Brunati AM, Marin O, et al. Tyrosine phosphorylation of protein kinase CK2 by Src-related tyrosine kinases correlates with increased catalytic activity. Biochem J 2003, 372: 841–849.Google Scholar
  69. 69.
    Lieberman DN, Mody I. Casein kinase-II regulates NMDA channel function in hippocampal neurons. Nat Neurosci 1999, 2: 125–132.Google Scholar
  70. 70.
    Tong G, Shepherd D, Jahr CE. Synaptic desensitization of NMDA receptors by calcineurin. Science 1995, 267: 1510–1512.Google Scholar
  71. 71.
    Venerando A, Ruzzene M, Pinna LA. Casein kinase: the triple meaning of a misnomer. Biochem J 2014, 460: 141–156.Google Scholar
  72. 72.
    Ma H, Chen SR, Chen H, Li L, Li DP, Zhou JJ, et al. alpha2delta-1 is essential for sympathetic output and NMDA receptor activity potentiated by angiotensin II in the hypothalamus. J Neurosci 2018, 38: 6388–6398.Google Scholar
  73. 73.
    Ma H, Chen SR, Chen H, Zhou JJ, Li DP, Pan HL. alpha2delta-1 couples to NMDA receptors in the hypothalamus to sustain sympathetic vasomotor activity in hypertension. J Physiol 2018, 596: 4269–4283.Google Scholar
  74. 74.
    Chen J, Li L, Chen SR, Chen H, Xie JD, Sirrieh RE, et al. The alpha2delta-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions. Cell Rep 2018, 22: 2307–2321.Google Scholar
  75. 75.
    Bowie D, Mayer ML. Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron 1995, 15: 453–462.Google Scholar
  76. 76.
    Donevan SD, Rogawski MA. Intracellular polyamines mediate inward rectification of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Proc Natl Acad Sci U S A 1995, 92: 9298–9302.Google Scholar
  77. 77.
    Isaac JT, Ashby MC, McBain CJ. The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 2007, 54: 859–871.Google Scholar
  78. 78.
    Hollmann M, Hartley M, Heinemann S. Ca2+ permeability of KA-AMPA–gated glutamate receptor channels depends on subunit composition. Science 1991, 252: 851–853.Google Scholar
  79. 79.
    Li DP, Byan HS, Pan HL. Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. J Neurosci 2012, 32: 372–380.Google Scholar
  80. 80.
    Li DP, Pan HL. Increased group I metabotropic glutamate receptor activity in paraventricular nucleus supports elevated sympathetic vasomotor tone in hypertension. Am J Physiol Regul Integr Comp Physiol 2010, 299: 552–561.Google Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Jing-Jing Zhou
    • 1
  • Hui-Jie Ma
    • 1
    • 2
  • Jian-Ying Shao
    • 1
  • Hui-Lin Pan
    • 1
  • De-Pei Li
    • 3
    Email author
  1. 1.Division of Anesthesiology and Critical CareThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of PhysiologyHebei Medical UniversityShijiazhuangChina
  3. 3.Department of Medicine, Center for Precision MedicineUniversity of MissouriColumbiaUSA

Personalised recommendations