Clinical Autonomic Research

, Volume 15, Issue 4, pp 254–263

Paraventricular nucleus, stress response, and cardiovascular disease



The paraventricular nucleus of the hypothalamus (PVN) is a complex effector structure that initiates endocrine and autonomic responses to stress. It receives inputs from visceral receptors, circulating hormones such as angiotensin II, and limbic circuits and contains neurons that release vasopressin, activate the adrenocortical axis, and activate preganglionic sympathetic or parasympathetic outflows. The neurochemical control of the different subgroups of PVN neurons is complex. The PVN has been implicated in the pathophysiology of congestive heart failure and the metabolic syndrome.

Key words

hypothalamus hypertension heart failure metabolic syndrome 


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  1. 1.
    Akine A, Montanaro M, Allen AM (2003) Hypothalamic paraventricular nucleus inhibition decreases renal sympathetic nerve activity in hypertensive and normotensive rats. Auton Neurosci 108:17–21CrossRefPubMedGoogle Scholar
  2. 2.
    Allen AM, Chai SY, Clevers J, McKinley MJ, Paxinos G, Mendelsohn FA (1988) Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata. J Comp Neurol 269:249–264CrossRefPubMedGoogle Scholar
  3. 3.
    Badoer E (2001) Hypothalamic paraventricular nucleus and cardiovascular regulation. Clin Exp Pharmacol Physiol 28:95–99CrossRefPubMedGoogle Scholar
  4. 4.
    Blair ML, Piekut D, Want A, Olschowka JA (1996) Role of the hypothalamic paraventricular nucleus in cardiovascular regulation. Clin Exp Pharmacol Physiol 23:161–165PubMedGoogle Scholar
  5. 5.
    Boudaba C, Di S, Tasker JG (2003) Presynaptic noradrenergic regulation of glutamate inputs to hypothalamic magnocellular neurones. J Neuroendocrinol 15:803–810PubMedGoogle Scholar
  6. 6.
    Buller KM, Dayas CV, Day TA (2003) Descending pathways from the paraventricular nucleus contribute to the recruitment of brainstem nuclei following a systemic immune challenge. Neuroscience 118:189–203CrossRefPubMedGoogle Scholar
  7. 7.
    Cato MJ, Toney GM (2005) Angiotensin II excites paraventricular nucleus neurons that innervate the rostral ventrolateral medulla: an in vitro patch-clamp study in brain slices. J Neurophysiol 93:403–413CrossRefPubMedGoogle Scholar
  8. 8.
    Cechetto DF, Saper CB (1988) Neurochemical organization of the hypothalamic projection to the spinal cord in the rat. J Comp Neurol 272:579–604CrossRefPubMedGoogle Scholar
  9. 9.
    Chen XQ, Du JZ, Wang YS (2004) Regulation of hypoxia-induced release of corticotropin-releasing factor in the rat hypothalamus by norepinephrine. Regul Pept 119:221–228CrossRefPubMedGoogle Scholar
  10. 10.
    Coote JH (1995) Cardiovascular function of the paraventricular nucleus of the hypothalamus. Biol Signals 4:142–149PubMedGoogle Scholar
  11. 11.
    Coote JH, Yang Z, Pyner S, Deering J (1998) Control of sympathetic outflows by the hypothalamic paraventricular nucleus. Clin Exp Pharmoc Physiol 25:461–463Google Scholar
  12. 12.
    Dampney RA, Horiuchi J, Tagawa T, Fontes MA, Potts PD, Polson JW (2003) Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone. Acta Physiol Scand 177:209–218CrossRefPubMedGoogle Scholar
  13. 13.
    Dampney RA, Polson JW, Potts PD, Hirooka Y, Horiuchi J (2003) Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression. Cell Mol Neurobiol 23:597–616CrossRefPubMedGoogle Scholar
  14. 14.
    Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96:748–753CrossRefPubMedGoogle Scholar
  15. 15.
    Elmquist JK (2001) Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. Int J Obes Relat Metab Disord 25(Suppl 5):S78–S82CrossRefPubMedGoogle Scholar
  16. 16.
    Engelmann M, Landgraf R, Wotjak CT (2004) The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: An old concept revisited. Front Neuroendocrinol 25:132–149CrossRefPubMedGoogle Scholar
  17. 17.
    Felder RB, Francis J, Zhang ZH, Wei SG, Weiss RM, Johnson AK (2003) Heart failure and the brain: new perspectives. Am J Physiol Regul Integr Comp Physiol 284:259–276Google Scholar
  18. 18.
    Ferguson AV, Bains JS, Lowes V (1992) Circumventricular organs and cardiovascular homeostasis. In: Kunos G, Ciriello J (eds) Central Neural Mechanisms in Cardiovascular Regulation Vol 2. Birkhauser, Basel, Switzerland, pp 80–101Google Scholar
  19. 19.
    Ferguson AV, Samson WK (2003) The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 24:141–150CrossRefPubMedGoogle Scholar
  20. 20.
    Ferguson AV, Wall KM (1992) Central actions of angiotensin in cardiovascular control: multiple roles for a single peptide. Can J Physiol Pharmacol 70:779–785PubMedGoogle Scholar
  21. 21.
    Goncharuk VD, Van Heerikhuize J, Swaab DF, Buijs RM (2002) Paraventricular nucleus of the human hypothalamus in primary hypertension: activation of corticotropin-releasing hormone neurons. J Comp Neurol 443:321–331CrossRefPubMedGoogle Scholar
  22. 22.
    Hallbeck M, Larhammar D, Blomqvist A (2001) Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord. J Comp Neurol 433:222–238CrossRefPubMedGoogle Scholar
  23. 23.
    Herman JP, Cullinan WE, Ziegler DR, Tasker JG (2002) Role of the paraventricular nucleus microenvironment in stress integration. Eur J Neurosci 16:381–385CrossRefPubMedGoogle Scholar
  24. 24.
    Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24:151–180CrossRefPubMedGoogle Scholar
  25. 25.
    Herman JP, Mueller NK, Figueiredo H (2004) Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci 1018:35–45CrossRefPubMedGoogle Scholar
  26. 26.
    Hjemdahl P (2002) Stress and the metabolic syndrome: an interesting but enigmatic association. Circulation 106:2634–2636CrossRefPubMedGoogle Scholar
  27. 27.
    Hussy N, Deleuze C, Desarmenien MG, Moos FC (2000) Osmotic regulation of neuronal activity: a new role for taurine and glial cells in a hypothalamic neuroendocrine structure. Prog Neurobiol 62:113–134CrossRefPubMedGoogle Scholar
  28. 28.
    Imaki T, Naruse M, Harada S, Chikada N, Nakajima K, Yoshimoto T, Demura H (1998) Stress-induced changes of gene expression in the paraventricular nucleus are enhanced in spontaneously hypertensive rats. J Neuroendocrinol 10:635–643CrossRefPubMedGoogle Scholar
  29. 29.
    Ito S, Komatsu K, Tsukamoto K, Kanmatsuse K, Sved AF (2002) Ventrolateral medulla AT1 receptors support blood pressure in hypertensive rats. Hypertension 40:552–559CrossRefPubMedGoogle Scholar
  30. 30.
    Jain P, Armando I, Juorio AV, Barden N, Benicky J, Saavedra JM (2004) Decreased hypothalamic and adrenal angiotensin II receptor expression and adrenomedullary catecholamines in transgenic mice with impaired glucocorticoid receptor function. Neuroendocrinology 80:171–180CrossRefPubMedGoogle Scholar
  31. 31.
    Jansen AS, Wessendorf MW, Loewy AD (1995) Transneuronal labeling of CNS neuropeptide and monoamine neurons after pseudorabies virus injections into the stellate ganglion. Brain Res 683:1–24CrossRefPubMedGoogle Scholar
  32. 32.
    Jedema HP, Grace AA (2004) Corticotropin-releasing hormone directly activates noradrenergic neurons of the locus ceruleus recorded in vitro. J Neurosci 24:9703–9713CrossRefPubMedGoogle Scholar
  33. 33.
    Jezova D, Ochedalski T, Kiss A, Aguilera G (1998) Brain angiotensin II modulates sympathoadrenal and hypothalamic pituitary adrenocortical activation during stress. J Neuroendocrinol 10:67–72CrossRefPubMedGoogle Scholar
  34. 34.
    Jhamandas JH, Renaud LP (1987) Neurophysiology of a central baroreceptor pathway projecting to hypothalamic vasopressin neurons. Can J Neurol Sci 14:17–24PubMedGoogle Scholar
  35. 35.
    Johns EJ (2005) Angiotensin in the brain and the autonomic control of the kidney. Exp Physiol 90:163–168CrossRefPubMedGoogle Scholar
  36. 36.
    Kadekaro M (2004) Nitric oxide modulation of the hypothalamo-neurohypophyseal system. Braz J Med Biol Res 37:441–450CrossRefPubMedGoogle Scholar
  37. 37.
    Kalra SP, Kalra PS (2004) NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. Neuropeptides 38:201–211CrossRefPubMedGoogle Scholar
  38. 38.
    Koutcherov Y, Mai JK, Ashwell KW, Paxinos G (2000) Organization of the human paraventricular hypothalamic nucleus. J Comp Neurol 423:299–318CrossRefPubMedGoogle Scholar
  39. 39.
    Ku YH, Li YH (2003) Subfornical organ-angiotensin II pressor system takes part in pressor response of emotional circuit. Peptides 24:1063–1067CrossRefPubMedGoogle Scholar
  40. 40.
    Latchford KJ, Ferguson AV (2004) ANG II-induced excitation of paraventricular nucleus magnocellular neurons: a role for glutamate interneurons. Am J Physiol Regul Integr Comp Physiol 286:R894–R902PubMedGoogle Scholar
  41. 41.
    Leng G, Brown CH, Russell JA (1999) Physiological pathways regulating the activity of magnocellular neurosecretory cells. Prog Neurobiol 57:625–655CrossRefPubMedGoogle Scholar
  42. 42.
    Li DP, Atnip LM, Chen SR, Pan HL (2005) Regulation of synaptic inputs to paraventricular-spinal output neurons by alpha2 adrenergic receptors. J Neurophysiol 93:393–402CrossRefPubMedGoogle Scholar
  43. 43.
    Li DP, Chen SR, Finnegan TF, Pan HL (2004) Signalling pathway of nitric oxide in synaptic GABA release in the rat paraventricular nucleus. J Physiol 554:100–110CrossRefPubMedGoogle Scholar
  44. 44.
    Li YF, Patel KP (2003) Paraventricular nucleus of the hypothalamus and elevated sympathetic activity in heart failure: the altered inhibitory mechanisms. Acta Physiol Scand 177:17–26CrossRefPubMedGoogle Scholar
  45. 45.
    Lindley TE, Doobay MF, Sharma RV, Davisson RL (2004) Superoxide is involved in the central nervous system activation and sympathoexcitation of myocardial infarction-induced heart failure. Circ Res 94:402–409CrossRefPubMedGoogle Scholar
  46. 46.
    Mark AL, Correia ML, Rahmouni K, Haynes WG (2002) Selective leptin resistance: a new concept in leptin physiology with cardiovascular implications. J Hypertens 20:1245–1250CrossRefPubMedGoogle Scholar
  47. 47.
    Mastorakos G, Zapanti E (2004) The hypothalamic-pituitary-adrenal axis in the neuroendocrine regulation of food intake and obesity: the role of corticotropin releasing hormone. Nutr Neurosci 7:271–280CrossRefPubMedGoogle Scholar
  48. 48.
    Matsumura K, Tsuchihashi T, Fujii K, Iida M (2003) Neural regulation of blood pressure by leptin and the related peptides. Regul Pept 114:79–86CrossRefPubMedGoogle Scholar
  49. 49.
    McKinley MJ, Allen AM, Mathai ML, May C, McAllen RM, Oldfield BJ, Weisinger RS (2001) Brain angiotensin and body fluid homeostasis. Jpn J Physiol 51:281–289CrossRefPubMedGoogle Scholar
  50. 50.
    McKinley MJ, Allen AM, May CN, McAllen RM, Oldfield BJ, Sly D, Mendelsohn FA (2001) Neural pathways from the lamina terminalis influencing cardiovascular and body fluid homeostasis. Clin Exp Pharmacol Physiol 28:990–992CrossRefPubMedGoogle Scholar
  51. 51.
    Miyakubo H, Hayashi Y, Tanaka J (2002) Enhanced response of subfornical organ neurons projecting to the hypothalamic paraventricular nucleus to angiotensin II in spontaneously hypertensive rats. Auton Neurosci 95:131–136CrossRefPubMedGoogle Scholar
  52. 52.
    Moore RY, Danchenko RL (2002) Paraventricular- subparaventricular hypothalamic lesions selectively affect circadian function. Chronobiol Int 19:345–360CrossRefPubMedGoogle Scholar
  53. 53.
    Muders F, Elsner D, Jandeleit K, Bahner U, Kromer EP, Kirst I, Riegger GA, Palkovits M (1997) Chronic ACE inhibition by quinapril modulates central vasopressinergic system. Cardiovasc Res 34:575–581CrossRefPubMedGoogle Scholar
  54. 54.
    Pacak K (2000) Stressor-specific activation of the hypothalamic-pituitary-adrenocortical axis. Physiol Res 49 (Suppl 1):S11–S17PubMedGoogle Scholar
  55. 55.
    Pacak K, Palkovits M (2001) Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 22:502–548CrossRefPubMedGoogle Scholar
  56. 56.
    Portillo F, Carrasco M, Vallo JJ (1998) Separate populations of neurons within the paraventricular hypothalamic nucleus of the rat project to vagal and thoracic autonomic preganglionic levels and express c-Fos protein induced by lithium chloride. J Chem Neuroanat 14:95–102CrossRefPubMedGoogle Scholar
  57. 57.
    Potts PD, Ludbrook J, Gillman-Gaspari TA, Horiuchi J, Dampney RA (2000) Activation of brain neurons following central hypervolaemia and hypovolaemia: contribution of baroreceptor and non-baroreceptor inputs. Neuroscience 95:499–511CrossRefPubMedGoogle Scholar
  58. 58.
    Qadri F, Arens T, Schwarz EC, Hauser W, Dendorfer A, Dominiak P (2003) Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension. J Hypertens 21:1687–1694CrossRefPubMedGoogle Scholar
  59. 59.
    Quan N, He L, Lai W (2003) Endothelial activation is an intermediate step for peripheral lipopolysaccharide induced activation of paraventricular nucleus. Brain Res Bull 59:447–452CrossRefPubMedGoogle Scholar
  60. 60.
    Rahmouni K, Correia ML, Haynes WG, Mark AL (2005) Obesity-associated hypertension: new insights into mechanisms. Hypertension 45:9–14CrossRefPubMedGoogle Scholar
  61. 61.
    Ranson RN, Motawei K, Pyner S, Coote JH (1998) The paraventricular nucleus of the hypothalamus sends efferents to the spinal cord of the rat that closely appose sympathetic preganglionic neurones projecting to the stellate ganglion. Exp Brain Res 120:164–172CrossRefPubMedGoogle Scholar
  62. 62.
    Renaud LP, Bourque CW (1991) Neurophysiology and neuropharmacology of hypothalamic magnocellular neurons secreting vasopressin and oxytocin. Prog Neurobiol 36:131–169CrossRefPubMedGoogle Scholar
  63. 63.
    Rosmond R (2005) Role of stress in the pathogenesis of the metabolic syndrome. Psychoneuroendocrinology 30:1–10CrossRefPubMedGoogle Scholar
  64. 64.
    Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Jezova M, Zhou J (2004) Brain angiotensin II, an important stress hormone: regulatory sites and therapeutic opportunities. Ann N Y Acad Sci 1018:76–84CrossRefPubMedGoogle Scholar
  65. 65.
    Saper CB (2002) The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu Rev Neurosci 25:433–469CrossRefPubMedGoogle Scholar
  66. 66.
    Sawchenko PE, Brown ER, Chan RKW, Ericsson A, Li HY, Roland BL, Kovacs KJ (1996) The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res 107:201–222PubMedGoogle Scholar
  67. 67.
    Sawchenko PE, Li HY, Ericsson A (2000) Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res 122:61–78PubMedGoogle Scholar
  68. 68.
    Shafton AD, Ryan A, Badoer E (1998) Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Brain Res 801:239–243CrossRefPubMedGoogle Scholar
  69. 69.
    Shih CD, Au LC, Chan JY (2003) Differential role of leptin receptors at the hypothalamic paraventricular nucleus in tonic regulation of food intake and cardiovascular functions. J Biomed Sci 10:367–378CrossRefPubMedGoogle Scholar
  70. 70.
    Sladek CD (2004) Vasopressin response to osmotic and hemodynamic stress: neurotransmitter involvement. Stress 7:85–90PubMedGoogle Scholar
  71. 71.
    Stern JE (2001) Electrophysiological and morphological properties of preautonomic neurones in the rat hypothalamic paraventricular nucleus. J Physiol 537:161–177CrossRefPubMedGoogle Scholar
  72. 72.
    Swaab DF (2003) Supraoptic and paraventricular nucleus (SON, PVN). In: Aminoff MJ, Boller F, Swaab DF (eds) The Human Hypothalamus: Basic and Clinical Aspects. Elsevier, AmsterdamGoogle Scholar
  73. 73.
    Swanson LW (1991) Biochemical switching in hypothalamic circuits mediating responses to stress (Review). Prog Brain Res 87:181–200PubMedGoogle Scholar
  74. 74.
    Toth ZE, Gallatz K, Fodor M, Palkovits M (1999) Decussations of the descending paraventricular pathways to the brainstem and spinal cord autonomic centers. J Comp Neurol 414:255–266CrossRefPubMedGoogle Scholar
  75. 75.
    van Dijk G, de Vries K, Benthem L, Nyakas C, Buwalda B, Scheurink AJ (2003) Neuroendocrinology of insulin resistance: metabolic and endocrine aspects of adiposity. Eur J Pharmacol 480:31–42CrossRefPubMedGoogle Scholar
  76. 76.
    Voisin DL, Bourque CW (2002) Integration of sodium and osmosensory signals in vasopressin neurons. Trends Neurosci 25:199–205CrossRefPubMedGoogle Scholar
  77. 77.
    Wang M (2005) The role of glucocorticoid action in the pathophysiology of the Metabolic Syndrome. Nutr Metab (Lond) 2:3CrossRefGoogle Scholar
  78. 78.
    Weber KT, Sun Y, Wodi LA,Munir A, Jahangir E, Ahokas RA, Gerling IC, Postlethwaite AE, Warrington KJ (2003) Toward a broader understanding of aldosterone in congestive heart failure. J Renin Angiotensin Aldosterone Syst 4:155–163PubMedGoogle Scholar
  79. 79.
    Weiss ML, Kenney MJ, Musch TI, Patel KP (2003) Modifications to central neural circuitry during heart failure. Acta Physiol Scand 177:57–67CrossRefPubMedGoogle Scholar
  80. 80.
    Yang Z, Coote JH (2003) Role of GABA and NO in the paraventricular nucleus-mediated reflex inhibition of renal sympathetic nerve activity following stimulation of right atrial receptors in the rat. Exp Physiol 88:335–342CrossRefPubMedGoogle Scholar
  81. 81.
    Zhang ZH, Felder RB (2004) Melanocortin receptors mediate the excitatory effects of blood-borne murine leptin on hypothalamic paraventricular neurons in rat. Am J Physiol Regul Integr Comp Physiol 286:R303–R310PubMedGoogle Scholar
  82. 82.
    Zhang ZH, Wei SG, Francis J, Felder RB (2003) Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins. Am J Physiol Regul Integr Comp Physiol 284:R916–R927PubMedGoogle Scholar
  83. 83.
    Zhu GQ, Gao L, Patel KP, Zucker IH, Wang W (2004) ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure. J Appl Physiol 97:1746–1754CrossRefPubMedGoogle Scholar
  84. 84.
    Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, Davisson RL (2002) Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 91:1038–1045CrossRefPubMedGoogle Scholar
  85. 85.
    Zucker IH, Schultz HD, Li YF, Wang Y, Wang W, Patel KP (2004) The origin of sympathetic outflow in heart failure: the roles of angiotensin II and nitric oxide. Prog Biophys Mol Biol 84:217–232CrossRefPubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2005

Authors and Affiliations

  1. 1.Mayo Clinic, Dept. of Neurology, 811 Guggenheim BuildingRochester (MN) 55905USA

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