Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses

Hypertension Research volume 43, pages 995–1005 (2020)Cite this article

Abstract

The nucleus tractus solitarius (NTS), paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM) are the most targeted regions of central blood pressure control studies. Glutamate and gamma-aminobutyric acid (GABA) interact within these brain regions to modulate blood pressure. The brain renin-angiotensin system also participates in central blood pressure control. Angiotensin II increases blood pressure through the stimulation of angiotensin II type 1 (AT1) receptors within the PVN and RVLM and attenuates baroreceptor sensitivity, resulting in elevated blood pressure within the NTS. Angiotensin II type 2 (AT2) receptors in cardiovascular control centers in the brain also appear to be involved in blood pressure control and counteract AT1 receptor-mediated effects. The current review is focused on the interaction of GABA with AT1 and AT2 receptors in the control of blood pressure within the RVLM, PVN and NTS. Within the NTS, GABA is released from local GABAergic interneurons that are stimulated by local AT1 receptors and mediates a hypertensive response. In contrast, the local increase in GABA levels observed after AT2 receptor stimulation within the RVLM, likely from GABAergic nerve endings originating in the caudal ventrolateral medulla, is important in the mediation of the hypotensive response. Preliminary results suggest that the hypertensive response to AT1 receptor stimulation within the RVLM is associated with a reduction in GABA release. The current experimental evidence therefore indicates that GABA is an important mediator of brainstem responses to AT1 and AT2 receptor stimulation and that increased GABA release may play a role in hypertensive and hypotensive responses, depending on the site of action.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Dupont AG, Brouwers S. Brain angiotensin peptides regulate sympathetic tone and blood pressure. J Hypertens. 2010;28:1599–610.

    Article  CAS  PubMed  Google Scholar 

  2. Farag E, Sessler DI, Ebrahim Z, Kurz A, Morgan J, Ahuja S, et al. The renin angiotensin system and the brain: new developments. J Clin Neurosci. 2017;46:1–8.

    Article  CAS  PubMed  Google Scholar 

  3. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006;7:335–46.

    Article  CAS  PubMed  Google Scholar 

  4. Steckelings UM, Kloet A, Sumners C. Centrally mediated cardiovascular actions of the angiotensin II type 2 receptor. Trends Endocrinol Metab. 2017;28:684–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pan HL. Brain angiotensin II and synaptic transmission. Neuroscientist. 2004;10:422–31.

    Article  CAS  PubMed  Google Scholar 

  6. McKinley MJ, McAllen RM, Davern P, Giles ME, Penschow J, Sunn N, et al. The sensory circumventricular organs of the mammalian brain. Adv Anat Embryol Cell Biol. 2003;172:1–122.

    Article  Google Scholar 

  7. Butcher KS, Cechetto DF. Receptors in lateral hypothalamic area involved in insular cortex sympathetic responses. Am J Physiol. 1998;275(2 Pt 2):H689–96.

    CAS  PubMed  Google Scholar 

  8. Dampney RA, Michelini LC, Li DP, Pan HL. Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states. Am J Physiol Heart Circ Physiol. 2018;315:H1200–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hatam M, Ganjkhani M. Effect of GABA(A) receptors in the rostral ventrolateral medulla on cardiovascular response to the activation of the bed nucleus of the stria terminalis in female ovariectomized rats. Iran J Med Sci. 2012;37:242–52.

    PubMed  PubMed Central  Google Scholar 

  10. Li YF, Jackson KL, Stern JE, Rabeler B, Patel KP. Interaction between glutamate and GABA systems in the integration of sympathetic outflow by the paraventricular nucleus of the hypothalamus. Am J Physiol Heart Circ Physiol. 2006;291:H2847–56.

    Article  CAS  PubMed  Google Scholar 

  11. Miyawaki T, Minson J, Arnolda L, Chalmers J, Llewellyn-Smith I, Pilowsky P. Role of excitatory amino acid receptors in cardiorespiratory coupling in ventrolateral medulla. Am J Physiol. 1996;271(5 Pt 2):R1221–30.

    CAS  PubMed  Google Scholar 

  12. Tasker JG, Boudaba C, Schrader LA. Local glutamatergic and GABAergic synaptic circuits and metabotropic glutamate receptors in the hypothalamic paraventricular and supraoptic nuclei. Adv Exp Med Biol. 1998;449:117–21.

    Article  CAS  PubMed  Google Scholar 

  13. Steckelings UM, Paulis L, Namsolleck P, Unger T. AT2 receptor agonists: hypertension and beyond. Curr Opin Nephrol Hypertens. 2012;21:142–6.

    Article  CAS  PubMed  Google Scholar 

  14. McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, et al. The brain renin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol. 2003;35:901–18.

    Article  CAS  PubMed  Google Scholar 

  15. Wright JW, Harding JW. The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. Pflug Arch. 2013;465:133–51.

    Article  CAS  Google Scholar 

  16. Sigmund CD, Diz DI, Chappell MC. No brain renin-angiotensin system: Deja vu all over again? Hypertension. 2017;69:1007–10.

    Article  CAS  PubMed  Google Scholar 

  17. van Thiel BS, Góes Martini A, Te Riet L, Severs D, Uijl E, Garrelds IM, et al. Brain renin-angiotensin system: does it exist? Hypertension. 2017;69:1136–44.

    Article  PubMed  CAS  Google Scholar 

  18. Lombard-Banek C, Yu Z, Swiercz AP, Marvar PJ, Nemes P. A microanalytical capillary electrophoresis mass spectrometry assay for quantifying angiotensin peptides in the brain. Anal Bioanal Chem. 2019;411:4661–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jackson L, Eldahshan W, Fagan SC, Ergul A. Within the brain: the renin angiotensin system. Int J Mol Sci. 2018;19:876.

    Article  CAS  PubMed Central  Google Scholar 

  20. Shan Z, Cuadra AE, Sumners C, Raizada MK. Characterization of a functional (pro)renin receptor in rat brain neurons. Exp Physiol. 2008;93:701–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharm Rev. 2000;52:415–72.

    PubMed  Google Scholar 

  22. Padia SH, Carey RM. AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function. Pflug Arch. 2013;465:99–110.

    Article  CAS  Google Scholar 

  23. Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE. Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci. 2011;121:297–303.

    Article  CAS  Google Scholar 

  24. Ganong WF. The brain renin-angiotensin system. Annu Rev Physiol. 1984;46:17–31.

    Article  CAS  PubMed  Google Scholar 

  25. Ganten D, Speck G. The brain renin-angiotensin system: a model for the synthesis of peptides in the brain. Biochem Pharmacol. 1978;27:2379–89.

    Article  CAS  PubMed  Google Scholar 

  26. Hu L, Zhu DN, Yu Z, Wang JQ, Sun ZJ, Yao T. Expression of angiotensin II type 1 (AT(1)) receptor in the rostral ventrolateral medulla in rats. J Appl Physiol. 2002;92:2153–61.

    Article  CAS  PubMed  Google Scholar 

  27. Buttler L, Ribeiro IM, Ferreira-Neto HC, Antunes VR. Angiotensin II acting on PVN induces sympathoexcitation and pressor responses via the PI3K-dependent pathway. Auton Neurosci. 2016;198:54–8.

    Article  CAS  PubMed  Google Scholar 

  28. Li YF, Wang W, Mayhan WG, Patel KP. Angiotensin-mediated increase in renal sympathetic nerve discharge within the PVN: role of nitric oxide. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1035–43.

    Article  CAS  PubMed  Google Scholar 

  29. Tagawa T, Horiuchi J, Potts PD, Dampney RA. Sympathoinhibition after angiotensin receptor blockade in the rostral ventrolateral medulla is independent of glutamate and gamma-aminobutyric acid receptors. J Auton Nerv Syst. 1999;77:21–30.

    Article  CAS  PubMed  Google Scholar 

  30. Aguilera G, Young WS, Kiss A, Bathia A. Direct regulation of hypothalamic corticotropin-releasing-hormone neurons by angiotensin II. Neuroendocrinology. 1995;61:437–44.

    Article  CAS  PubMed  Google Scholar 

  31. Li DP, Chen SR, Pan HL. Angiotensin II stimulates spinally projecting paraventricular neurons through presynaptic disinhibition. J Neurosci. 2003;23:5041–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cato MJ, Toney GM. Angiotensin II excites paraventricular nucleus neurons that innervate the rostral ventrolateral medulla: an in vitro patch-clamp study in brain slices. J Neurophysiol. 2005;93:403–13.

    Article  CAS  PubMed  Google Scholar 

  33. Li DP, Pan HL. Angiotensin II attenuates synaptic GABA release and excites paraventricular-rostral ventrolateral medulla output neurons. J Pharm Exp Ther. 2005;313:1035–45.

    Article  CAS  Google Scholar 

  34. de Kloet AD, Krause EG, Scott KA, Foster MT, Herman JP, Sakai RR, et al. Central angiotensin II has catabolic action at white and brown adipose tissue. Am J Physiol Endocrinol Metab. 2011;301:E1081–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. de Kloet AD, Wang L, Pitra S, Hiller H, Smith JA, Tan Y, et al. A unique “angiotensin-sensitive” neuronal population coordinates neuroendocrine, cardiovascular, and behavioral responses to stress. J Neurosci. 2017;37:3478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Benicky J, Hafko R, Sanchez-Lemus E, Aguilera G, Saavedra JM. Six commercially available angiotensin II AT1 receptor antibodies are non-specific. Cell Mol Neurobiol. 2012;32:1353–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Herrera M, Sparks MA, Alfonso-Pecchio AR, Harrison-Bernard LM, Coffman TM. Lack of specificity of commercial antibodies leads to misidentification of angiotensin type 1 receptor protein. Hypertension. 2013;61:253–8.

    Article  CAS  PubMed  Google Scholar 

  38. Oldfield BJ, Davern PJ, Giles ME, Allen AM, Badoer E, McKinley MJ. Efferent neural projections of angiotensin receptor (AT1) expressing neurones in the hypothalamic paraventricular nucleus of the rat. J Neuroendocrinol. 2001;13:139–46.

    CAS  PubMed  Google Scholar 

  39. Wang L, Hiller H, Smith JA, de Kloet AD, Krause EG. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus control cardiovascular reactivity and anxiety-like behavior in male mice. Physiological Genomics. 2016;48:667–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Isegawa K, Hirooka Y, Katsuki M, Kishi T, Sunagawa K. Angiotensin II type 1 receptor expression in astrocytes is upregulated leading to increased mortality in mice with myocardial infarction-induced heart failure. Am J Physiol Heart Circ Physiol. 2014;307:H1448–55.

    Article  CAS  PubMed  Google Scholar 

  41. Sun H, Wu H, Yu X, Zhang R, Zhan S, Wang H, et al. Angiotensin II and its receptor in activated microglia enhanced neuronal loss and cognitive impairment following pilocarpine-induced status epilepticus. Mol Cell Neurosci. 2015;65:58–67.

    Article  CAS  PubMed  Google Scholar 

  42. Biancardi VC, Stranahan AM, Krause EG, de Kloet AD, Stern JE. Cross talk between AT1 receptors and Toll-like receptor 4 in microglia contributes to angiotensin II-derived ROS production in the hypothalamic paraventricular nucleus. Am J Physiol Heart Circ Physiol. 2016;310:H404–15.

    Article  PubMed  Google Scholar 

  43. Stern JE, Son S, Biancardi VC, Zheng H, Sharma N, Patel KP. Astrocytes contribute to angiotensin II stimulation of hypothalamic neuronal activity and sympathetic outflow. Hypertension. 2016;68:1483–93.

    Article  CAS  PubMed  Google Scholar 

  44. Zhou X, Yang H, Song X, Wang J, Shen L, Wang J. Central blockade of the AT1 receptor attenuates pressor effects via reduction of glutamate release and downregulation of NMDA/AMPA receptors in the rostral ventrolateral medulla of rats with stress-induced hypertension. Hypertens Res. 2019;42:1142–51.

    Article  CAS  PubMed  Google Scholar 

  45. Légat L. The role of brain AT1 and AT2 receptors in the regulation of blood pressure: interaction with glutamate, GABA and NO. Doctoral Thesis, VUBPRESS Brussels University Press: Vrije Universiteit Brussel. 2019.

  46. Mendelsohn FA, Allen AM, Clevers J, Denton DA, Tarjan E, McKinley MJ. Localization of angiotensin II receptor binding in rabbit brain by in vitro autoradiography. J Comp Neurol. 1988;270:372–84.

    Article  CAS  PubMed  Google Scholar 

  47. Phillips MI, Sumners C. Angiotensin II in central nervous system physiology. Regul Pept. 1998;78:1–11.

    Article  CAS  PubMed  Google Scholar 

  48. Labandeira-Garcia JL, Rodriguez-Perez AI, Garrido-Gil P, Rodriguez-Pallares J, Lanciego JL, Guerra MJ. Brain renin-angiotensin system and microglial polarization: implications for aging and neurodegeneration. Front Aging Neurosci. 2017;9:129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Lenkei Z, Palkovits M, Corvol P, Llorens-Cortès C. Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Front Neuroendocrinol. 1997;18:383–439.

    Article  CAS  PubMed  Google Scholar 

  50. Gonzalez AD, Wang G, Waters EM, Gonzales KL, Speth RC, Van Kempen TA, et al. Distribution of angiotensin type 1a receptor-containing cells in the brains of bacterial artificial chromosome transgenic mice. Neuroscience. 2012;226:489–509.

    Article  CAS  PubMed  Google Scholar 

  51. Lenkei Z, Corvol P, Llorens-Cortes C. Comparative expression of vasopressin and angiotensin type-1 receptor mRNA in rat hypothalamic nuclei: a double in situ hybridization study. Brain Res Mol Brain Res. 1995;34:135–42.

    Article  CAS  PubMed  Google Scholar 

  52. Guimond MO, Gallo-Payet N. The angiotensin II type 2 receptor in brain functions: an update. Int J Hypertens. 2012;2012:351758.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C. Distribution of angiotensin II type-2 receptor (AT2) mRNA expression in the adult rat brain. J Comp Neurol. 1996;373:322–39.

    Article  CAS  PubMed  Google Scholar 

  54. Sumners C, Alleyne A, Rodriguez V, Pioquinto DJ, Ludn JA, Kar S, et al. Brain angiotensin type-1 and type-2 receptors: cellular locations under normal and hypertensive conditions. Hypertens Res. 2019;43:281–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Oldfield BJ, Allen AM, Hards DK, McKinley MJ, Schlawe I, Mendelsohn FA. Distribution of angiotensin II receptor binding in the spinal cord of the sheep. Brain Res. 1994;650:40–8.

    Article  CAS  PubMed  Google Scholar 

  56. Healy DP, Rettig R, Nguyen T, Printz MP. Quantitative autoradiography of angiotensin II receptors in the rat solitary-vagal area: effects of nodose ganglionectomy or sinoaortic denervation. Brain Res. 1989;484:1–12.

    Article  CAS  PubMed  Google Scholar 

  57. Rettig R, Healy DP, Printz MP. Cardiovascular effects of microinjections of angiotensin II into the nucleus tractus solitarii. Brain Res. 1986;364:233–40.

    Article  CAS  PubMed  Google Scholar 

  58. Yang SN, Lippoldt A, Jansson A, Phillips MI, Ganten D, Fuxe K. Localization of angiotensin II AT1 receptor-like immunoreactivity in catecholaminergic neurons of the rat medulla oblongata. Neuroscience. 1997;81:503–15.

    Article  CAS  PubMed  Google Scholar 

  59. Casto R, Phillips MI. Cardiovascular actions of microinjections of angiotensin II in the brain stem of rats. Am J Physiol. 1984;246(5 Pt 2):R811–6.

    CAS  PubMed  Google Scholar 

  60. Tan PS, Killinger S, Horiuchi J, Dampney RA. Baroreceptor reflex modulation by circulating angiotensin II is mediated by AT1 receptors in the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2267–78.

    Article  CAS  PubMed  Google Scholar 

  61. Yao F, Sumners C, O’Rourke ST, Sun C. Angiotensin II increases GABAB receptor expression in nucleus tractus solitarii of rats. Am J Physiol Heart Circ Physiol. 2008;294:H2712–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang Q, Yao F, O’Rourke ST, Qian SY, Sun C. Angiotensin II enhances GABA(B) receptor-mediated responses and expression in nucleus tractus solitarii of rats. Am J Physiol Heart Circ Physiol. 2009;297:H1837–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Speretta GF, Ruchaya PJ, Delbin MA, Melo MR, Li H, Menani JV, et al. Importance of AT1 and AT2 receptors in the nucleus of the solitary tract in cardiovascular responses induced by a high-fat diet. Hypertens Res. 2019;42:439–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Meyer JM, Felten DL, Weyhenmeyer JA. Measurement of immunoreactive angiotensin II levels in microdissected brain nuclei from developing spontaneously hypertensive and Wistar Kyoto rats. Exp Neurol. 1990;107:164–9.

    Article  CAS  PubMed  Google Scholar 

  65. Raizada MK, Sumners C, Lu D. Angiotensin II type 1 receptor mRNA levels in the brains of normotensive and spontaneously hypertensive rats. J Neurochem. 1993;60:1949–52.

    Article  CAS  PubMed  Google Scholar 

  66. Shan Z, Zubcevic J, Shi P, Jun JY, Dong Y, Murça TM, et al. Chronic knockdown of the nucleus of the solitary tract AT1 receptors increases blood inflammatory-endothelial progenitor cell ratio and exacerbates hypertension in the spontaneously hypertensive rat. Hypertension. 2013;61:1328–33.

    Article  CAS  PubMed  Google Scholar 

  67. Ferguson AV, Washburn DL, Latchford KJ. Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function. Exp Biol Med. 2001;226:85–96.

    Article  CAS  Google Scholar 

  68. Matsumura K, Averill DB, Ferrario CM. Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex. Am J Physiol. 1998;275(5 Pt 2):R1611–9.

    CAS  PubMed  Google Scholar 

  69. Tan PS, Potas JR, Killinger S, Horiuchi J, Goodchild AK, Pilowsky PM, et al. Angiotensin II evokes hypotension and renal sympathoinhibition from a highly restricted region in the nucleus tractus solitarii. Brain Res. 2005;1036:70–6.

    Article  CAS  PubMed  Google Scholar 

  70. Wong LF, Polson JW, Murphy D, Paton JF, Kasparov S. Genetic and pharmacological dissection of pathways involved in the angiotensin II-mediated depression of baroreflex function. FASEB J. 2002;16:1595–601.

    Article  CAS  PubMed  Google Scholar 

  71. Averill DB, Diz DI. Angiotensin peptides and baroreflex control of sympathetic outflow: pathways and mechanisms of the medulla oblongata. Brain Res Bull. 2000;51:119–28.

    Article  CAS  PubMed  Google Scholar 

  72. Bailey TW, Appleyard SM, Jin YH, Andresen MC. Organization and properties of GABAergic neurons in solitary tract nucleus (NTS). J Neurophysiol. 2008;99:1712–22.

    Article  PubMed  Google Scholar 

  73. Zubcevic J, Potts JT. Role of GABAergic neurones in the nucleus tractus solitarii in modulation of cardiovascular activity. Exp Physiol. 2010;95:909–18.

    Article  CAS  PubMed  Google Scholar 

  74. Paton JF, Boscan P, Murphy D, Kasparov S. Unravelling mechanisms of action of angiotensin II on cardiorespiratory function using in vivo gene transfer. Acta Physiol Scand. 2001;173:127–37.

    Article  CAS  PubMed  Google Scholar 

  75. Dufour A, Tell F, Baude A. Perinatal development of inhibitory synapses in the nucleus tractus solitarii of the rat. Eur J Neurosci. 2010;32:538–49.

    Article  PubMed  Google Scholar 

  76. Potts JT, Paton JF, Mitchell JH, Garry MG, Kline G, Anguelov PT, et al. Contraction-sensitive skeletal muscle afferents inhibit arterial baroreceptor signalling in the nucleus of the solitary tract: role of intrinsic GABA interneurons. Neuroscience. 2003;119:201–14.

    Article  CAS  PubMed  Google Scholar 

  77. Mei L, Zhang J, Mifflin S. Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract. Am J Physiol Regul Integr Comp Physiol. 2003;285:R1276–86.

    Article  CAS  PubMed  Google Scholar 

  78. Vitela M, Mifflin SW. gamma-Aminobutyric acid(B) receptor-mediated responses in the nucleus tractus solitarius are altered in acute and chronic hypertension. Hypertension. 2001;37(2 Pt 2):619–22.

    Article  CAS  PubMed  Google Scholar 

  79. Légat L, Smolders I, Dupont AG. AT1 receptor mediated hypertensive response to Ang II in the nucleus tractus solitarii of normotensive rats involves NO dependent local GABA release. Front Pharmacol. 2019;10:460.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Millatt LJ, Abdel-Rahman EM, Siragy HM. Angiotensin II and nitric oxide: a question of balance. Regul Pept. 1999;81:1–10.

    Article  CAS  PubMed  Google Scholar 

  81. Dun NJ, Dun SL, Forstermann U. Nitric oxide synthase immunoreactivity in rat pontine medullary neurons. Neuroscience. 1994;59:429–45.

    Article  CAS  PubMed  Google Scholar 

  82. Dun NJ, Dun SL, Hwang LL, Forstermann U. Infrequent co-existence of nitric oxide synthase and parvalbumin, calbindin and calretinin immunoreactivity in rat pontine neurons. Neurosci Lett. 1995;191:165–8.

    Article  CAS  PubMed  Google Scholar 

  83. Paton JF, Wang S, Polson JW, Kasparov S. Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension. J Mol Med. 2008;86:705–10.

    Article  CAS  PubMed  Google Scholar 

  84. Paton JF, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S. Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol. 2001;531(Pt 2):445–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li DP, Chen SR, Pan HL. Nitric oxide inhibits spinally projecting paraventricular neurons through potentiation of presynaptic GABA release. J Neurophysiol. 2002;88:2664–74.

    Article  CAS  PubMed  Google Scholar 

  86. Li DP, Chen SR, Finnegan TF, Pan HL. Signalling pathway of nitric oxide in synaptic GABA release in the rat paraventricular nucleus. J Physiol. 2004;554(Pt 1):100–10.

    Article  CAS  PubMed  Google Scholar 

  87. Li Y, Zhang W, Stern JE. Nitric oxide inhibits the firing activity of hypothalamic paraventricular neurons that innervate the medulla oblongata: role of GABA. Neuroscience. 2003;118:585–601.

    Article  CAS  PubMed  Google Scholar 

  88. de Kloet AD, Wang L, Ludin JA, Smith JA, Pioquinto DJ, Hiller H, et al. Reporter mouse strain provides a novel look at angiotensin type-2 receptor distribution in the central nervous system. Brain Struct Funct. 2016;221:891–912.

    Article  PubMed  CAS  Google Scholar 

  89. Dai SY, Zhang YP, Peng W, Shen Y, He JJ. Central infusion of angiotensin II type 2 receptor agonist compound 21 attenuates DOCA/NaCl-induced hypertension in female rats. Oxid Med Cell Longev. 2016;2016:3981790.

    Article  PubMed  CAS  Google Scholar 

  90. Brouwers S, Smolders I, Wainford RD, Dupont AG. Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats. Clin Sci. 2015;129:81–92.

    Article  CAS  Google Scholar 

  91. de Kloet AD, Steckelings UM, Sumners C. Protective angiotensin type 2 receptors in the brain and hypertension. Curr Hypertens Rep. 2017;19:46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci USA. 1999;96:6506–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yang R, Smolders I, Vanderheyden P, Demaegdt H, Van Eeckhaut A, Vauquelin G, et al. Pressor and renal hemodynamic effects of the novel angiotensin A peptide are angiotensin II type 1A receptor dependent. Hypertension. 2011;57:956–64.

    Article  CAS  PubMed  Google Scholar 

  94. Gao L, Wang W, Li H, Sumners C, Zucker IH. Effects of angiotensin type 2 receptor overexpression in the rostral ventrolateral medulla on blood pressure and urine excretion in normal rats. Hypertension. 2008;51:521–7.

    Article  CAS  PubMed  Google Scholar 

  95. Légat L, Brouwers S, Smolders IJ, Dupont AG. Hypotensive response to angiotensin II type 2 receptor stimulation in the rostral ventrolateral medulla requires functional GABA-A receptors. Front Neurosci. 2017;11:346.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Kishi T, Hirooka Y, Sakai K, Shigematsu H, Shimokawa H, Takeshita A. Overexpression of eNOS in the RVLM causes hypotension and bradycardia via GABA release. Hypertension. 2001;38:896–901.

    Article  CAS  PubMed  Google Scholar 

  97. Shinohara K, Hirooka Y, Kishi T, Sunagawa K. Reduction of nitric oxide-mediated gamma-amino butyric acid release in rostral ventrolateral medulla is involved in superoxide-induced sympathoexcitation of hypertensive rats. Circ J. 2012;76:2814–21.

    Article  CAS  PubMed  Google Scholar 

  98. Abdulla MH, Johns EJ. Nitric oxide impacts on angiotensin AT2 receptor modulation of high-pressure baroreflex control of renal sympathetic nerve activity in anaesthetized rats. Acta Physiol. 2014;210:832–44.

    Article  CAS  Google Scholar 

  99. Legat L, Smolders IJ, Dupont AG. Investigation of the role of AT2 receptors in the nucleus tractus solitarii of normotensive rats in blood pressure control. Front Neurosci. 2019;13:589.

    Article  PubMed  PubMed Central  Google Scholar 

  100. de Kloet AD, Pitra S, Wang L, Hiller H, Pioquinto DJ, Smith JA, et al. Angiotensin type-2 receptors influence the activity of vasopressin neurons in the paraventricular nucleus of the hypothalamus in male mice. Endocrinology. 2016;157:3167–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Shraim N, Mertens B, Clinckers R, Sarre S, Michotte Y, Van Eeckhaut A. Microbore liquid chromatography with UV detection to study the in vivo passage of compound 21, a non-peptidergic AT2 receptor agonist, to the striatum in rats. J Neurosci Methods. 2011;202:137–42.

    Article  CAS  PubMed  Google Scholar 

  102. Gao L, Wang WZ, Wang W, Zucker IH. Imbalance of angiotensin type 1 receptor and angiotensin II type 2 receptor in the rostral ventrolateral medulla: potential mechanism for sympathetic overactivity in heart failure. Hypertension. 2008;52:708–14.

    Article  CAS  PubMed  Google Scholar 

  103. AbdAlla S, Lother H, Abdel-tawab AM, Quitterer U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem. 2001;276:39721–6.

    Article  CAS  PubMed  Google Scholar 

  104. Horiuchi M, Hayashida W, Akishita M, Tamura K, Daviet L, Lehtonen JY, et al. Stimulation of different subtypes of angiotensin II receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Circ Res. 1999;84:876–82.

    Article  CAS  PubMed  Google Scholar 

  105. Sumners C, Zhu M, Gelband CH, Posner P. Angiotensin II type 1 receptor modulation of neuronal K+ and Ca2+ currents: intracellular mechanisms. Am J Physiol. 1996;271:C154–63.

    Article  CAS  PubMed  Google Scholar 

  106. Gelband CH, Warth JD, Mason HS, Zhu M, Moore JM, Kenyon JL, et al. Angiotensin II type 1 receptor-mediated inhibition of K+ channel subunit kv2.2 in brain stem and hypothalamic neurons. Circ Res. 1999;84:352–9.

    Article  CAS  PubMed  Google Scholar 

  107. Li YW, Polson JW, Dampney RA. Angiotensin II excites vasomotor neurons but not respiratory neurons in the rostral and caudal ventrolateral medulla. Brain Res. 1992;577:161–4.

    Article  CAS  PubMed  Google Scholar 

  108. Li YW, Guyenet PG. Neuronal excitation by angiotensin II in the rostral ventrolateral medulla of the rat in vitro. Am J Physiol. 1995;268(1 Pt 2):R272–7.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Research Group Experimental Pharmacology (EFAR), Center for Neurosciences, (C4N) Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels, 1090, Belgium

    Alain G. Dupont & Laura Légat

Authors
  1. Alain G. Dupont
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Légat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura Légat.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dupont, A.G., Légat, L. GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses. Hypertens Res 43, 995–1005 (2020). https://doi.org/10.1038/s41440-020-0470-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-020-0470-9

Keywords

This article is cited by

Search

Advanced search

Quick links