Skip to main content
SpringerLink
Log in

Chronic Intracerebroventricular Infusion of Metformin Inhibits Salt-Sensitive Hypertension via Attenuation of Oxidative Stress and Neurohormonal Excitation in Rat Paraventricular Nucleus

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Metformin (MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension. This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus (PVN). Salt-sensitive rats received a high-salt (HS) diet to induce hypertension, or a normal-salt (NS) diet as control. At the same time, they received intracerebroventricular (ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure (MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity, reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in salt-sensitive hypertension via attenuating oxidative stress, inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Grassi G. Role of the sympathetic nervous system in human hypertension. J Hypertens 1998, 16: 1979–1987.

    Article  CAS  Google Scholar 

  2. de Wardener HE. The hypothalamus and hypertension. Physiol Rev 2001, 81: 1599–1658.

    Article  Google Scholar 

  3. Swanson LW, Sawchenko PE. Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. Neuroendocrinology 1980, 31: 410–417.

    Article  CAS  Google Scholar 

  4. Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007, 292: 82–97.

    Article  Google Scholar 

  5. Datla SR, Griendling KK. Reactive oxygen species, NADPH oxidases, and hypertension. Hypertension 2010, 56: 325–330.

    Article  CAS  Google Scholar 

  6. Braga VA, Medeiros IA, Ribeiro TP, Franca-Silva MS, Botelho-Ono MS, Guimaraes DD. Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: implications in neurogenic hypertension. Braz J Med Biol Res 2011, 44: 871–876.

    Article  CAS  Google Scholar 

  7. Wang G, Coleman CG, Chan J, Faraco G, Marques-Lopes J, Milner TA, et al. Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons. Am J Physiol Regul Integr Comp Physiol 2013, 304: 1096–1106.

    Article  Google Scholar 

  8. Veerasingham SJ, Raizada MK. Brain renin-angiotensin system dysfunction in hypertension: recent advances and perspectives. Br J Pharmacol 2003, 139: 191–202.

    Article  CAS  Google Scholar 

  9. Takahashi H, Yoshika M, Komiyama Y, Nishimura M. The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain. Hypertens Res 2011, 34: 1147–1160.

    Article  CAS  Google Scholar 

  10. Kang YM, Yang Q, Yu XJ, Qi J, Zhang Y, Li HB, et al. Hypothalamic paraventricular nucleus activation contributes to neurohumoral excitation in rats with heart failure. Regen Med Res 2014, 2: 2.

    Article  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis 2017, 27: 657–669.

    Article  CAS  Google Scholar 

  14. Gomez-Garcia A, Martinez Torres G, Ortega-Pierres LE, Rodriguez-Ayala E, Alvarez-Aguilar C. Rosuvastatin and metformin decrease inflammation and oxidative stress in patients with hypertension and dyslipidemia. Rev Esp Cardiol 2007, 60: 1242–1249.

    Article  Google Scholar 

  15. He H, Zhao Z, Chen J, Ni Y, Zhong J, Yan Z, et al. Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial. J Hypertens 2012, 30: 1430–1439.

    Article  CAS  Google Scholar 

  16. Tain YL, Wu KLH, Lee WC, Leu S, Chan JYH. Prenatal metformin therapy attenuates hypertension of developmental origin in male adult offspring exposed to maternal high-fructose and post-weaning high-fat diets. Int J Mol Sci 2018, 3: 19. pii: E1066.

  17. Duan Q, Song P, Ding Y, Zou MH. Activation of AMP-activated protein kinase by metformin ablates angiotensin II-induced endoplasmic reticulum stress and hypertension in mice in vivo. Br J Pharmacol 2017, 174: 2140–2151.

    Article  CAS  Google Scholar 

  18. Hamidi Shishavan M, Henning RH, van Buiten A, Goris M, Deelman LE, Buikema H. Metformin improves endothelial function and reduces blood pressure in diabetic spontaneously hypertensive rats independent from glycemia control: comparison to vildagliptin. Sci Rep 2017, 7: 10975.

    Article  Google Scholar 

  19. Muntzel MS, Abe A, Petersen JS. Effects of adrenergic, cholinergic and ganglionic blockade on acute depressor responses to metformin in spontaneously hypertensive rats. J Pharmacol Exp Ther 1997, 281: 618–623.

    CAS  PubMed  Google Scholar 

  20. Petersen JS, DiBona GF. Acute sympathoinhibitory actions of metformin in spontaneously hypertensive rats. Hypertension 1996, 27: 619–625.

    Article  CAS  Google Scholar 

  21. Labuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopien B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2010, 62: 956–965.

    Article  CAS  Google Scholar 

  22. Lv WS, Wen JP, Li L, Sun RX, Wang J, Xian YX, et al. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res 2012, 1444: 11–19.

    Article  CAS  Google Scholar 

  23. Coleman BR, Carlezon WA Jr, Myers KM. Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist. Neurosci Lett 2013, 541: 39–42.

    Article  CAS  Google Scholar 

  24. Petersen JS, Andersen D, Muntzel MS, Diemer NH, Holstein-Rathlou NH. Intracerebroventricular metformin attenuates salt-induced hypertension in spontaneously hypertensive rats. Am J Hypertens 2001, 14: 1116–1122.

  25. 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.

    Article  CAS  Google Scholar 

  26. Qi J, Yu XJ, Shi XL, Gao HL, Yi QY, Tan H, et al. NF-kappaB blockade in hypothalamic paraventricular nucleus inhibits high-salt-induced hypertension through NLRP3 and caspase-1. Cardiovasc Toxicol 2016, 16: 345–354.

    Article  CAS  Google Scholar 

  27. Su Q, Huo CJ, Li HB, Liu KL, Li X, Yang Q, et al. Renin-angiotensin system acting on reactive oxygen species in paraventricular nucleus induces sympathetic activation via AT1R/PKCγ/Rac1 pathway in salt-induced hypertension. Sci Rep 2017, 7: 43107.

    Article  CAS  Google Scholar 

  28. Li HB, Qin DN, Cheng K, Su Q, Miao YW, Guo J, et al. Central blockade of salusin β attenuates hypertension and hypothalamic inflammation in spontaneously hypertensive rats. Sci Rep 2015, 5: 11162.

    Article  CAS  Google Scholar 

  29. Su YT, Gu MY, Chu X, Feng X, Yu YQ. Whole-brain mapping of direct inputs to and axonal projections from GABAergic neurons in the parafacial zone. Neurosci Bull 2018, 34:485–496.

    Article  CAS  Google Scholar 

  30. Zhang M, Qin DN, Suo YP, Su Q, Li HB, Miao YW, et al. Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension. Toxicol Lett 2015, 235: 206–215.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. 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.

    Article  CAS  Google Scholar 

  33. Rodrigo R, Gonzalez J, Paoletto F. The role of oxidative stress in the pathophysiology of hypertension. Hypertens Res 2011, 34: 431–440.

    Article  CAS  Google Scholar 

  34. Fujita M, Ando K, Nagae A, Fujita T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension 2007, 50: 360–367.

    Article  CAS  Google Scholar 

  35. Blaustein MP, Leenen FH, Chen L, Golovina VA, Hamlyn JM, Pallone TL, et al. How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension. Am J Physiol Heart Circ Physiol 2012, 302: 1031–1049.

    Article  Google Scholar 

  36. Gabor A, Leenen FH. Mechanisms mediating sodium-induced pressor responses in the PVN of Dahl rats. Am J Physiol Regul Integr Comp Physiol 2011, 301: 1338–1349.

    Article  Google Scholar 

  37. Gao L, Wang W, Li YL, Schultz HD, Liu D, Cornish KG, et al. Superoxide mediates sympathoexcitation in heart failure: roles of angiotensin II and NAD(P)H oxidase. Circ Res 2004, 95: 937–944.

    Article  CAS  Google Scholar 

  38. Zhang Y, Yu Y, Zhang F, Zhong MK, Shi Z, Gao XY, et al. NAD(P)H oxidase in paraventricular nucleus contributes to the effect of angiotensin II on cardiac sympathetic afferent reflex. Brain Res 2006, 1082: 132–141.

    Article  CAS  Google Scholar 

  39. Hernandez JS, Barreto-Torres G, Kuznetsov AV, Khuchua Z, Javadov S. Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria. J Cell Mol Med 2014, 18: 709–720.

    Article  CAS  Google Scholar 

  40. Mahrouf M, Ouslimani N, Peynet J, Djelidi R, Couturier M, Therond P, et al. Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase C. Biochem Pharmacol 2006, 72: 176–183.

    Article  CAS  Google Scholar 

  41. Jacintho JD, Kovacic P. Neurotransmission and neurotoxicity by nitric oxide, catecholamines, and glutamate: unifying themes of reactive oxygen species and electron transfer. Curr Med Chem 2003, 10: 2693–2703.

    Article  CAS  Google Scholar 

  42. Sorce S, Schiavone S, Tucci P, Colaianna M, Jaquet V, Cuomo V, et al. The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses. J Neurosci 2010, 30: 11317–11325.

    Article  CAS  Google Scholar 

  43. Zhou FM, Cheng RX, Wang S, Huang Y, Gao YJ, Zhou Y, et al. Antioxidants attenuate acute and chronic itch: peripheral and central mechanisms of oxidative stress in pruritus. Neurosci Bull 2017, 33: 423–435.

    Article  CAS  Google Scholar 

  44. Cole RL, Sawchenko PE. Neurotransmitter regulation of cellular activation and neuropeptide gene expression in the paraventricular nucleus of the hypothalamus. J Neurosci 2002, 22: 959–969.

    Article  CAS  Google Scholar 

  45. 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.

    Article  CAS  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. 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: 2847–2856.

    Article  Google Scholar 

  48. Martins-Pinge MC, Mueller PJ, Foley CM, Heesch CM, Hasser EM. Regulation of arterial pressure by the paraventricular nucleus in conscious rats: interactions among glutamate, GABA, and nitric oxide. Front Physiol 2012, 3: 490.

    PubMed  Google Scholar 

  49. Pavlov TS, Levchenko V, Ilatovskaya DV, Li H, Palygin O, Pastor-Soler NM, et al. Lack of effects of metformin and AICAR chronic infusion on the development of hypertension in Dahl salt-sensitive rats. Front Physiol 2017, 8: 227.

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Jian-Jun Mu (Department of Cardiology, The First Affiliated Hospital of Xi’an Jiaotong University) for providing the Dahl salt-sensitive rats. This work was supported by the National Natural Science Foundation of China (81600333, 81770426, 81800372, 91439120, and 91639105), the Postdoctoral Science Foundation of China (2016M602835, 2017M620457), and the Postdoctoral Science Foundation of Shaanxi Province, China (2016BSHEDZZ91).

Author information

Author notes

  1. Xiao-Jing Yu, Ya-Nan Zhao and Yi-Kang Hou have contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, Xi’an Jiaotong University School of Basic Medical Sciences, Ministry of Education Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, 710061, China

    Xiao-Jing Yu, Ya-Nan Zhao, Hong-Bao Li, Wen-Jie Xia, Hong-Li Gao, Kai-Li Liu, Qing Su, Ying Li & Yu-Ming Kang

  2. Department of Cardiology, Second Affiliated Hospital of Shanxi Medical University, Taiyuan, 030001, China

    Hui-Yu Yang, Bin Liang & Zhi-Ming Yang

  3. Department of Respiratory Medicine, Affiliated Jiangyin Hospital of Southeast University Medical School, Jiangyin, 214400, China

    Ya-Nan Zhao

  4. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Wen-Sheng Chen

  5. Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, China

    Wei Cui

  6. Department of Plastic and Cosmetic Surgery, Gansu Provincial Hospital, Lanzhou, 730000, China

    Yi-Kang Hou

  7. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, 210029, China

    Guo-Qing Zhu

Authors
  1. Xiao-Jing Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ya-Nan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi-Kang Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Bao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Jie Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong-Li Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kai-Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qing Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hui-Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bin Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wen-Sheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Guo-Qing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Zhi-Ming Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yu-Ming Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ying Li, Zhi-Ming Yang or Yu-Ming Kang.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, XJ., Zhao, YN., Hou, YK. et al. Chronic Intracerebroventricular Infusion of Metformin Inhibits Salt-Sensitive Hypertension via Attenuation of Oxidative Stress and Neurohormonal Excitation in Rat Paraventricular Nucleus. Neurosci. Bull. 35, 57–66 (2019). https://doi.org/10.1007/s12264-018-0308-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-018-0308-5

Keywords

Search

Navigation