Neuroscience Bulletin

, Volume 35, Issue 1, pp 47–56 | Cite as

Blockade of Endogenous Angiotensin-(1–7) in Hypothalamic Paraventricular Nucleus Attenuates High Salt-Induced Sympathoexcitation and Hypertension

  • Xiao-Jing Yu
  • Yu-Wang Miao
  • Hong-Bao Li
  • Qing Su
  • Kai-Li Liu
  • Li-Yan Fu
  • Yi-Kang Hou
  • Xiao-Lian Shi
  • Ying Li
  • Jian-Jun Mu
  • Wen-Sheng Chen
  • Wei Cui
  • Guo-Qing Zhu
  • Philip J. Ebenezer
  • Joseph FrancisEmail author
  • Yu-Ming KangEmail author
Original Article


Angiotensin (Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1–7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1–7) in the PVN, through modulation of PICs and oxidative stress.


High-salt diet Hypertension Angiotensin-(1–7) Paraventricular nucleus Pro-inflammatory cytokines 



This work was supported by the National Natural Science Foundation of China (81600333, 81770426, 91439120, and 91639105), the China Postdoctoral Science Foundation (2016M602835 and 2016M592802), and the Shaanxi Postdoctoral Science Foundation (2016BSHEDZZ91).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Cardinale JP, Sriramula S, Mariappan N, Agarwal D, Francis J. Angiotensin II-induced hypertension is modulated by nuclear factor-kappaB in the paraventricular nucleus. Hypertension 2012, 59: 113–121.CrossRefGoogle Scholar
  2. 2.
    Davisson RL. Physiological genomic analysis of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2003, 285: 498–511.CrossRefGoogle Scholar
  3. 3.
    Iyer SN, Chappell MC, Averill DB, Diz DI, Ferrario CM. Vasodepressor actions of angiotensin-(1–7) unmasked during combined treatment with lisinopril and losartan. Hypertension 1998, 31: 699–705.CrossRefGoogle Scholar
  4. 4.
    Kohara K, Brosnihan KB, Chappell MC, Khosla MC, Ferrario CM. Angiotensin-(1–7). A member of circulating angiotensin peptides. Hypertension 1991, 17: 131–138.CrossRefGoogle Scholar
  5. 5.
    Xu P, Sriramula S, Lazartigues E. ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol 2011, 300: 804–817.CrossRefGoogle Scholar
  6. 6.
    Han Y, Sun HJ, Li P, Gao Q, Zhou YB, Zhang F, et al. Angiotensin-(1–7) in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats. PLoS One 2012, 7: e48966.CrossRefGoogle Scholar
  7. 7.
    Ehlers PI, Nurmi L, Turpeinen AM, Korpela R, Vapaatalo H. Casein-derived tripeptide Ile-Pro-Pro improves angiotensin-(1–7)- and bradykinin-induced rat mesenteric artery relaxation. Life Sci 2011, 88: 206–211.CrossRefGoogle Scholar
  8. 8.
    Qi Y, Shenoy V, Wong F, Li H, Afzal A, Mocco J, et al. Lentivirus-mediated overexpression of angiotensin-(1–7) attenuated ischaemia-induced cardiac pathophysiology. Exp Physiol 2011, 96: 863–874.CrossRefGoogle Scholar
  9. 9.
    Zhou LM, Shi Z, Gao J, Han Y, Yuan N, Gao XY, et al. Angiotensin-(1–7) and angiotension II in the rostral ventrolateral medulla modulate the cardiac sympathetic afferent reflex and sympathetic activity in rats. Pflugers Arch 2010, 459: 681–688.CrossRefGoogle Scholar
  10. 10.
    Sun HJ, Li P, Chen WW, Xiong XQ, Han Y. Angiotensin II and angiotensin-(1–7) in paraventricular nucleus modulate cardiac sympathetic afferent reflex in renovascular hypertensive rats. PLoS One 2012, 7: 52557.CrossRefGoogle Scholar
  11. 11.
    Ambuhl P, Felix D, Imboden H, Khosla MC, Ferrario CM. Effects of angiotensin analogues and angiotensin receptor antagonists on paraventricularneurones. Regul Pept 1992, 38: 111–120.CrossRefGoogle Scholar
  12. 12.
    Ambuhl P, Felix D, Khosla MC. [7-D-ALA]-angiotensin-(1–7): selective antagonism of angiotensin-(1–7) in the rat paraventricular nucleus. Brain Res Bull 1994, 35: 289–291.CrossRefGoogle Scholar
  13. 13.
    Silva AQ, Santos RA, Fontes MA. Blockade of endogenous angiotensin-(1–7) in the hypothalamic paraventricular nucleus reduces renal sympathetic tone. Hypertension 2005, 46: 341–348.CrossRefGoogle Scholar
  14. 14.
    Block CH, Santos RA, Brosnihan KB, Ferrario CM. Immunocytochemical localization of angiotensin-(1–7) in the rat forebrain. Peptides 1988, 9: 1395–1401.CrossRefGoogle Scholar
  15. 15.
    Gironacci MM, Brosnihan KB, Ferrario CM, Gorzalczany S, Verrilli MA, Pascual M, et al. Increased hypothalamic angiotensin-(1–7) levels in rats with aortic coarctation-induced hypertension. Peptides 2007, 28: 1580–1585.CrossRefGoogle Scholar
  16. 16.
    Becker LK, Etelvino GM, Walther T, Santos RA, Campagnole-Santos MJ. Immunofluorescence localization of the receptor Mas in cardiovascular-related areas of the rat brain. Am J Physiol Heart CircPhysiol 2007, 293: 1416–1424.CrossRefGoogle Scholar
  17. 17.
    Kang YM, Ma Y, Zheng JP, Elks C, Sriramula S, Yang ZM, et al. Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovasc Res 2009, 82: 503–512.CrossRefGoogle Scholar
  18. 18.
    Kang YM, Wang Y, Yang LM, Elks C, Cardinale J, Yu XJ, et al. TNF-alpha in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters. Tohoku J Exp Med 2010, 222: 251–263.CrossRefGoogle Scholar
  19. 19.
    Bai J, Yu XJ, Liu KL, Wang FF, Li HB, Shi XL, et al. Tert-butylhydroquinone attenuates oxidative stress and inflammation in hypothalamic paraventricular nucleus in high salt-induced hypertension. Toxicol Lett 2017, 281: 1–9.CrossRefGoogle Scholar
  20. 20.
    Kang YM, Ma Y, Elks C, Zheng JP, Yang ZM, Francis J. Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: role of nuclear factor-kappaB. Cardiovasc Res 2008, 79: 671–678.CrossRefGoogle Scholar
  21. 21.
    Qi J, Yu XJ, Shi XL, Gao HL, Yi QY, Tan H, et al. NF-κB blockade in hypothalamic paraventricular nucleus inhibits high-salt-induced hypertension through NLRP3 and Caspase-1. Cardiovasc Toxicol 2015, 16: 345–354.CrossRefGoogle Scholar
  22. 22.
    Li HB, Qin DN, Ma L, Miao YW, Zhang DM, Lu Y, et al. Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension. Toxicol Appl Pharmacol 2014, 279: 141–149.CrossRefGoogle Scholar
  23. 23.
    Liu D, Gao L, Roy SK, Cornish KG, Zucker IH. Role of oxidant stress on AT1 receptor expression in neurons of rabbits with heart failure and in cultured neurons. Circ Res 2008, 103: 186–193.CrossRefGoogle Scholar
  24. 24.
    Braga VA, Colombari E, Jovita MG. Angiotensin II-derived reactive oxygen species underpinning the processing of the cardiovascular reflexes in the medulla oblongata. Neurosci Bull 2011, 27: 269–274.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefGoogle Scholar
  26. 26.
    Sriramula S, Cardinale JP, Francis J. Inhibition of TNF in the brain reverses alterations in RAS components and attenuates angiotensin II-induced hypertension. PLoS One 2013, 8: 63847.CrossRefGoogle Scholar
  27. 27.
    Kang YM, He RL, Yang LM, Qin DN, Guggilam A, Elks C, et al. Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovasc Res 2009, 83: 737–746.CrossRefGoogle Scholar
  28. 28.
    Sun W, Wang X, Hou C, Yang L, Li H, Guo J, et al. Oleuropein improves mitochondrial function to attenuate oxidative stress by activating the Nrf2 pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats. Neuropharmacology 2017, 113: 556–566.CrossRefGoogle Scholar
  29. 29.
    Yu XJ, Suo YP, Qi J, Yang Q, Li HH, Zhang DM, et al. Interaction between AT1 receptor and NF-kappaB in hypothalamic paraventricular nucleus contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure. Cardiovasc Toxicol 2013, 13: 381–390.CrossRefGoogle Scholar
  30. 30.
    Kang YM, Zhang AQ, Zhao XF, Cardinale JP, Elks C, Cao XM, et al. Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure. Basic Res Cardiol 2011, 106: 473–483.CrossRefGoogle Scholar
  31. 31.
    Bai J, Yu XJ, Liu KL, Wang FF, Jing GX, Li HB, et al. Central administration of tert-butylhydroquinone attenuates hypertension via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus of hypertensive rats. Toxicol Appl Pharmacol 2017, 333: 100–109.CrossRefGoogle Scholar
  32. 32.
    Kang YM, Gao F, Li HH, Cardinale JP, Elks C, Zang WJ, et al. NF-kappaB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure. Basic Res Cardiol 2011, 106: 1087–1097.CrossRefGoogle Scholar
  33. 33.
    Miller FJ Jr, Gutterman DD, Rios CD, Heistad DD, Davidson BL. Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis. Circ Res 1998, 82: 1298–1305.CrossRefGoogle Scholar
  34. 34.
    Kang YM, Zhang ZH, Johnson RF, Yu Y, Beltz T, Johnson AK, et al. Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circ Res 2006, 99: 758–766.CrossRefGoogle Scholar
  35. 35.
    Agarwal D, Welsch MA, Keller JN, Francis J. Chronic exercise modulates RAS components and improves balance between pro- and anti-inflammatory cytokines in the brain of SHR. Basic Res Cardiol 2011, 106: 1069–1085.CrossRefGoogle Scholar
  36. 36.
    Mariappan N, Elks CM, Sriramula S, Guggilam A, Liu Z, Borkhsenious O, et al. NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res 2010, 85: 473–483.CrossRefGoogle Scholar
  37. 37.
    Li Z, You Z, Li M, Pang L, Cheng J, Wang L. Protective effect of resveratrol on the brain in a rat model of epilepsy. Neurosci Bull 2017, 33: 273–280.CrossRefGoogle Scholar
  38. 38.
    Zimmerman MC, Lazartigues E, Lang JA, Sinnayah P, Ahmad IM, Spitz DR, et al. Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 2002, 91: 1038–1045.CrossRefGoogle Scholar
  39. 39.
    Ding L, Zhang LL, Gao R, Chen D, Wang JJ, Gao XY, et al. Superoxide anions in paraventricular nucleus modulate adipose afferent reflex and sympathetic activity in rats. PLoS One 2013, 8: 83771.CrossRefGoogle Scholar
  40. 40.
    Zhu GQ, Gao L, Patel KP, Zucker IH, Wang W. ANG II in the paraventricular nucleus potentiates the cardiac sympathetic afferent reflex in rats with heart failure. J Appl Physiol (1985) 2004, 97: 1746–1754.Google Scholar
  41. 41.
    Gorbea-Oppliger VJ, Fink GD. Cerebroventricular injection of angiotensin II antagonist: effects on blood pressure responses to central and systemic angiotensin II. J Pharmacol Exp Ther 1995, 273: 611–616.Google Scholar
  42. 42.
    Gomes da Silva AQ, Xavier CH, Campagnole-Santos MJ, Caligiorne SM, Baltatu OC, Bader M, et al. Cardiovascular responses evoked by activation or blockade of GABA(A) receptors in the hypothalamic PVN are attenuated in transgenic rats with low brain angiotensinogen. Brain Res 2012, 1448: 101–110.CrossRefGoogle Scholar
  43. 43.
    Han Y, Fan ZD, Yuan N, Xie GQ, Gao J, De W, et al. Superoxide anions in the paraventricular nucleus mediate the enhanced cardiac sympathetic afferent reflex and sympathetic activity in renovascular hypertensive rats. J Appl Physiol (1985) 2011, 110: 646–652.Google Scholar
  44. 44.
    Shi P, Diez-Freire C, Jun JY, Qi Y, Katovich MJ, Li Q, et al. Brain microglial cytokines in neurogenic hypertension. Hypertension 2010, 56: 297–303.CrossRefGoogle Scholar
  45. 45.
    Shi Z, Gan XB, Fan ZD, Zhang F, Zhou YB, Gao XY, et al. Inflammatory cytokines in paraventricular nucleus modulate sympathetic activity and cardiac sympathetic afferent reflex in rats. Acta Physiol (Oxf) 2011, 203: 289–297.CrossRefGoogle Scholar
  46. 46.
    Francis J, Wei SG, Weiss RM, Felder RB. Brain angiotensin-converting enzyme activity and autonomic regulation in heart failure. Am J Physiol Heart Circ Physiol 2004, 287: 2138–2146.CrossRefGoogle Scholar
  47. 47.
    Kang YM, Zhang DM, Yu XJ, Yang Q, Qi J, Su Q, et al. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines. Toxicol Appl Pharmacol 2014, 274: 436–444.CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Xiao-Jing Yu
    • 1
  • Yu-Wang Miao
    • 1
    • 3
  • Hong-Bao Li
    • 1
  • Qing Su
    • 1
  • Kai-Li Liu
    • 1
  • Li-Yan Fu
    • 1
  • Yi-Kang Hou
    • 4
  • Xiao-Lian Shi
    • 5
  • Ying Li
    • 1
  • Jian-Jun Mu
    • 6
  • Wen-Sheng Chen
    • 7
  • Wei Cui
    • 8
  • Guo-Qing Zhu
    • 9
  • Philip J. Ebenezer
    • 2
  • Joseph Francis
    • 2
    Email author
  • Yu-Ming Kang
    • 1
    Email author
  1. 1.Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to DiseasesMinistry of EducationXi’anChina
  2. 2.Comparative Biomedical Sciences, School of Veterinary MedicineLouisiana State UniversityBaton RougeUSA
  3. 3.Genetic Engineering Laboratory, College of BiotechnologyXi’an UniversityXi’anChina
  4. 4.Department of Plastic and Cosmetic SurgeryGansu Provincial HospitalLanzhouChina
  5. 5.Department of Pharmacology, School of Basic Medical SciencesXi’an Jiaotong University Health Science CenterXi’anChina
  6. 6.Department of Cardiovascular MedicineFirst Affiliated Hospital of the Medical College of Xi’an Jiaotong UniversityXi’anChina
  7. 7.Department of Cardiovascular SurgeryXijing Hospital, Fourth Military Medical UniversityXi’anChina
  8. 8.Department of Endocrinology and Metabolism, The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an Jiaotong University Health Science CenterXi’anChina
  9. 9.Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of PhysiologyNanjing Medical UniversityNanjingChina

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