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.

  • Article
  • Published:

Systemic administration of pentoxifylline attenuates the development of hypertension in renovascular hypertensive rats

Hypertension Research volume 43, pages 667–678 (2020)Cite this article

Abstract

There is evidence to suggest that hypertension involves a chronic low-grade systemic inflammatory response; however, the underlying mechanisms are unclear. To further understand the role of inflammation in hypertension, we used a rat renovascular model of hypertension in which we administered the TNF-α synthesis inhibitor pentoxifylline (PTX, 30 mg/kg/day) in the drinking water for 60 days. In conscious rats, PTX administration significantly attenuated the development of hypertension (systolic blood pressure, PTX: 145 ± 8 vs. vehicle (Veh): 235 ± 11 mmHg, after 38 days of treatment, P < 0.05, N = 5/group). This attenuation in hypertension was coupled with a decrease in the low-frequency spectra of systolic blood pressure variability (PTX: 1.23 ± 0.2 vs Veh: 3.05 ± 0.8 arbitrary units, P < 0.05, N = 5/group). Furthermore, systemic PTX administration decreased c-Fos expression within the hypothalamic paraventricular nucleus (PTX: 17 ± 4 vs. Veh: 70 ± 13 cells, P < 0.01, N = 5, PVN) and increased the total number of microglial branches (PTX: 2129 ± 242 vs. Veh: 1415 ± 227 branches, P < 0.05, N = 4/group). Acute central injection of PTX (20 μg) under urethane anesthesia caused a small transient decrease in blood pressure but did not change renal sympathetic nerve activity. Surprisingly, we found no detectable basal levels of plasma TNF-α in either PTX- or vehicle-treated animals. These results suggest that inflammation plays a role in renovascular hypertension and that PTX might act both peripherally and centrally to prevent hypertension.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Navar LG, Zou L, Thun Von A, Tarng Wang C, Imig JD, Mitchell KD. Unraveling the mystery of Goldblatt hypertension. N. Physiol Sci. 1998;13:170–6.

    CAS  Google Scholar 

  2. Oliveira-Sales EB, Nishi EE, Carillo BA, Boim MA, Dolnikoff MS, Bergamaschi CT, et al. Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension. Am J Hypertens. 2009;22:484–92. https://doi.org/10.1038/ajh.2009.17

    Article  CAS  PubMed  Google Scholar 

  3. Guyenet PG, Stornetta RL, Holloway BB, Souza GMPR, Abbott SBG. Rostral ventrolateral medulla and hypertension. Hypertension. 2018;72:559–66. https://doi.org/10.1161/HYPERTENSIONAHA.118.10921

  4. Wu KLH, Chan SHH, Chan JYH. Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation. J Neuroinflammation. 2012;9:212. https://doi.org/10.1186/1742-2094-9-212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Oliveira-Sales EB, Toward MA, Campos RR, Paton JFR. Revealing the role of the autonomic nervous system in the development and maintenance of Goldblatt hypertension in rats. Auton Neurosci. 2014;183:23–9. https://doi.org/10.1016/j.autneu.2014.02.001

    Article  PubMed  PubMed Central  Google Scholar 

  6. Oliveira-Sales EB, Colombari E, Abdala AP, Campos RR, Paton JFR. Sympathetic overactivity occurs before hypertension in the two‐kidney, one‐clip model. Exp Physiol. 2016;101:67–80. https://doi.org/10.1113/EP085390

    Article  PubMed  Google Scholar 

  7. Cachofeiro V, Miana M, Heras NDL, Martín-Fernandez B, Ballesteros S, Balfagon G, et al. Inflammation: a link between hypertension and atherosclerosis. CHYR. 2009;5:40–8. https://doi.org/10.2174/157340209787314333

    Article  CAS  Google Scholar 

  8. Stefanadi E, Tousoulis D, Androulakis ES, Papageorgiou N, Charakida M, Siasos G, et al. Inflammatory markers in essential hypertension: potential clinical implications. Curr Vasc Pharm. 2010;8:509–16.

    Article  CAS  Google Scholar 

  9. Waki H, Gouraud SS, Maeda M, Paton JFR. Evidence of specific inflammatory condition in nucleus tractus solitarii of spontaneously hypertensive rats. Exp Physiol. 2010;95:595–600. https://doi.org/10.1113/expphysiol.2009.047324

    Article  CAS  PubMed  Google Scholar 

  10. 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. https://doi.org/10.1161/HYPERTENSIONAHA.110.150409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zubcevic J, Waki H, Raizada MK, Paton JFR. Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension. Hypertension. 2011;57:1026–33. https://doi.org/10.1161/HYPERTENSIONAHA.111.169748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA. Pentoxifylline for intermittent claudication. Cochrane Database Syst Rev. 2015;9:CD005262. https://doi.org/10.1002/14651858.CD005262.pub3

    Article  PubMed  Google Scholar 

  13. Zabel P, Schade FU, Schlaak M. Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology. 1993;187:447–63. https://doi.org/10.1016/S0171-2985(11)80356-6

    Article  CAS  PubMed  Google Scholar 

  14. Vakili A, Mojarrad S, Akhavan MM, Rashidy-Pour A. Pentoxifylline attenuates TNF-α protein levels and brain edema following temporary focal cerebral ischemia in rats. Brain Res. 2011;1377:119–25. https://doi.org/10.1016/j.brainres.2011.01.001

    Article  CAS  PubMed  Google Scholar 

  15. Brie D, Sahebkar A, Penson PE, Dinca M, Ursoniu S, Serban M-C, et al. Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Hypertens. 2016;34:1–2329. https://doi.org/10.1097/HJH.0000000000001086

    Article  CAS  Google Scholar 

  16. Azhar A, El-Bassossy HM. Pentoxifylline alleviates hypertension in metabolic syndrome: effect on low-grade inflammation and angiotensin system. J Endocrinol Investig. 2015;38:437–45. https://doi.org/10.1007/s40618-014-0209-z

    Article  CAS  Google Scholar 

  17. Goldblatt H, Lynch J, Hanzal RF, Summerville WW. Studies on experimental hypertension: I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med. 1934;59:347–79.

    Article  CAS  Google Scholar 

  18. National Health and Medical Research Council. Australian code for the care and use of animals for scientific purposes. Canberra, Australia: National Health and Medical Research Council; 2013.

  19. Korim WS, Elsaafien K, Basser JR, Setiadi A, May CN, Yao ST. In renovascular hypertension, TNF-α type-1 receptors in the area postrema mediate increases in cardiac and renal sympathetic nerve activity and blood pressure. Cardiovasc Rese. 2018; https://doi.org/10.1093/cvr/cvy268

  20. Hildreth CM, Padley JR, Pilowsky PM, Goodchild AK. Impaired serotonergic regulation of heart rate may underlie reduced baroreflex sensitivity in an animal model of depression. Am J Physiol Heart Circ Physiol 2008;294:H474–80.

    Article  CAS  Google Scholar 

  21. Tasić T, Djordjević DM, De Luka SR, Trbovich AM, Japundžić-Žigon N. Static magnetic field reduces blood pressure short-term variability and enhances baro-receptor reflex sensitivity in spontaneously hypertensive rats. Int J Radiat Biol 2017;93:527–34.

    Article  Google Scholar 

  22. Morrison HW, Filosa JA. A quantitative spatiotemporal analysis of microglia morphology during ischemic stroke and reperfusion. J Neuroinflammation. 2013;10:4. https://doi.org/10.1186/1742-2094-10-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Winklewski PJ, Radkowski M, Demkow U. Neuroinflammatory mechanisms of hypertension: potential therapeutic implications. Curr Opin Nephrol Hypertension. 2016;25:410–6. https://doi.org/10.1097/MNH.0000000000000250

    Article  CAS  Google Scholar 

  24. Bivol LM, Berge RK, Iversen BM. Tetradecylthioacetic acid prevents the inflammatory response in two-kidney, one-clip hypertension. Am J Physiol Regul Integr Comp Physiol. 2008;294:R438–47. https://doi.org/10.1152/ajpregu.00590.2007

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Z-H, Wei S-G, Francis J, Felder RB. Cardiovascular and renal sympathetic activation by blood-borne TNF-alpha in rat: the role of central prostaglandins. Am J Physiol Regul Integr Comp Physiol. 2003;284:R916–27. https://doi.org/10.1152/ajpregu.00406.2002

    Article  CAS  PubMed  Google Scholar 

  26. Rodriguez R, Lee A, Mathis KW, Broome HJ, Thorwald M, Martinez B, et al. Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats. Am J Physiol Ren Physiol. 2018;315:F1081–90. https://doi.org/10.1152/ajprenal.00156.2018

    Article  CAS  Google Scholar 

  27. 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:e63847. https://doi.org/10.1371/journal.pone.0063847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. El-Bassossy HM, El-Moselhy MA, Mahmoud MF. Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition. Naunyn Schmiedebergs Arch Pharm. 2011;384:277–85. https://doi.org/10.1007/s00210-011-0669-z

    Article  CAS  Google Scholar 

  29. Shi Z, Jiang S-J, Wang G-H, Xu A-L, Guo L. Pro-inflammatory cytokines in paraventricular nucleus mediate the cardiac sympathetic afferent reflex in hypertension. Auton Neurosci. 2014;186:54–61. https://doi.org/10.1016/j.autneu.2014.10.001

    Article  CAS  PubMed  Google Scholar 

  30. Jung J-Y, Lee J-U, Kim W-J. Enhanced activity of central adrenergic neurons in two-kidney, one clip hypertension in Sprague-Dawley rats. Neurosci Lett. 2004;369:14–8. https://doi.org/10.1016/j.neulet.2004.07.029

    Article  CAS  PubMed  Google Scholar 

  31. Zubcevic J, Santisteban MM, Perez PD, Arocha R, Hiller H, Malphurs WL, et al. A single angiotensin II hypertensive stimulus is associated with prolonged neuronal and immune system activation in Wistar-Kyoto rats. Front Physiol. 2017;8:592–11. https://doi.org/10.3389/fphys.2017.00592

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kang Y-M, Ma Y, Zheng J-P, Elks C, Sriramula S, Yang Z-M, et al. Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension. Cardiovasc Res. 2009;82:cvp073–512. https://doi.org/10.1093/cvr/cvp073

    Article  CAS  Google Scholar 

  33. Xia D-Y, Zhang H-S, Wu L-Y, Zhang X-S, Zhou M-L, Hang C-H. Pentoxifylline alleviates early brain injury after experimental subarachnoid hemorrhage in rats: possibly via inhibiting TLR 4/NF-κB signaling pathway. Neurochem Res. 2017;42:963–74. https://doi.org/10.1007/s11064-016-2129-0

    Article  CAS  PubMed  Google Scholar 

  34. Li H-B, Li X, Huo C-J, Su Q, Guo J, Yuan Z-Y, et al. TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension. Toxicol Appl Pharm. 2016;305:93–102. https://doi.org/10.1016/j.taap.2016.06.014

    Article  CAS  Google Scholar 

  35. Gan Z, Huang D, Jiang J, Li Y, Li H, Ke Y. Captopril alleviates hypertension-induced renal damage, inflammation, and NF-κB activation. Braz J Med Biol Res. 2018;51:e7338. https://doi.org/10.1590/1414-431X20187338

    Article  PubMed  PubMed Central  Google Scholar 

  36. Purkayastha S, Zhang G, Cai D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-[beta] and NF-[kappa]B. Nat Med. 2011;17:883–7. https://doi.org/10.1038/nm.2372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Carvalho-Galvão A, Guimarães DD, De Brito Alves JL, Braga VA. Central INhibition of Tumor Necrosis Factor alpha reduces hypertension by attenuating oxidative stress in the rostral ventrolateral medulla in renovascular hypertensive rats. Front Physiol. 2019;10:491. https://doi.org/10.3389/fphys.2019.00491

    Article  PubMed  PubMed Central  Google Scholar 

  38. Shih R-H, Wang C-Y, Yang C-M. NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci. 2015;8:77. https://doi.org/10.3389/fnmol.2015.00077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014;40:274–88. https://doi.org/10.1016/j.immuni.2014.01.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Johns EJ, Kopp UC, DiBona GF. Neural control of renal function. Compr Physiol. 2011;1:731–67. https://doi.org/10.1002/cphy.c100043

    Article  PubMed  Google Scholar 

  41. Osborn JW, Foss JD. Renal nerves and long-term control of arterial pressure. Compr Physiol. 2017;7:263–320. https://doi.org/10.1002/cphy.c150047

    Article  PubMed  Google Scholar 

  42. Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inflammation, Immunity, and Hypertension. Hypertension. 2011;57:132–40. https://doi.org/10.1161/HYPERTENSIONAHA.110.163576

    Article  CAS  PubMed  Google Scholar 

  43. Zheng H, Patel KP. Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow. Auton Neurosci. 2017;204:57–64. https://doi.org/10.1016/j.autneu.2016.08.008

    Article  PubMed  Google Scholar 

  44. Plotnikov MB, Aliev OI, Shamanaev AY, Sidekhmenova AV, Anfinogenova Y, Anishchenko AM, et al. Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development. Clin Exp Hypertens. 2017;39:570–8. https://doi.org/10.1080/10641963.2017.1291662

    Article  CAS  PubMed  Google Scholar 

  45. Song X-A, Jia L-L, Cui W, Zhang M, Chen W, Yuan Z-Y, et al. Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats. Toxicol Appl Pharm. 2014;281:101–8. https://doi.org/10.1016/j.taap.2014.09.004

    Article  CAS  Google Scholar 

  46. deBoer RW, Karemaker JM, Strackee J. Hemodynamic fluctuations and baroreflex sensitivity in humans: a beat-to-beat model. Am J Physiol Heart circulatory Physiol. 1987;253:H680–9. https://doi.org/10.1152/ajpheart.1987.253.3.H680

    Article  CAS  Google Scholar 

  47. Madwed JB, Albrecht P, Mark RG, Cohen RJ. Low-frequency oscillations in arterial pressure and heart rate: a simple computer model. Am J Physiol Heart circulatory Physiol. 1989;256:H1573–9. https://doi.org/10.1152/ajpheart.1989.256.6.H1573

    Article  CAS  Google Scholar 

  48. Gooch JL, Sharma AC. Targeting the immune system to treat hypertension: where are we? Curr Opin Nephrol Hypertension. 2014;23:473–9. https://doi.org/10.1097/MNH.0000000000000052

    Article  CAS  Google Scholar 

  49. Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, Ghofrani HA, Weissmann N, et al. cAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases. Circulation. 2011;123:1194–204. https://doi.org/10.1161/CIRCULATIONAHA.110.941484

    Article  CAS  PubMed  Google Scholar 

  50. Hermann M, Flammer A, Lüscher TF. Nitric oxide in hypertension. J Clin Hypertens. 2006;8:17–29.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia (GNT 1079680 to STY and GNT 1128108 to CMN and STY), the High Blood Pressure Research Council of Australia and the Rebecca L Cooper Medical Foundation (to WSK). AS is supported by the Australian Government Research Training Program Scholarship. STY is supported by an Australian Research Council Future Fellowship (FT170100363).

Author information

Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, 3010, Australia

    Anthony Setiadi, Willian S. Korim, Clive N. May & Song T. Yao

  2. Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, 3010, Australia

    Song T. Yao

Authors
  1. Anthony Setiadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Willian S. Korim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clive N. May
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Song T. Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Song T. Yao.

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

Setiadi, A., Korim, W.S., May, C.N. et al. Systemic administration of pentoxifylline attenuates the development of hypertension in renovascular hypertensive rats. Hypertens Res 43, 667–678 (2020). https://doi.org/10.1038/s41440-020-0412-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-020-0412-6

Keywords

This article is cited by

Search

Advanced search

Quick links