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:

Electrical stimulation of the carotid sinus lowers arterial pressure and improves heart rate variability in l-NAME hypertensive conscious rats

Hypertension Research volume 43, pages 1057–1067 (2020)Cite this article

A Comment to this article was published on 22 July 2020

Abstract

We evaluated the effects of long-term (48 h) electrical stimulation of the carotid sinus (CS) in hypertensive rats. l-NAME-treated (10 days) Wistar rats were implanted with a catheter in the femoral artery and a miniaturized electrical stimulator attached to electrodes positioned around the left CS, encompassing the CS nerve. One day after implantation, arterial pressure (AP) was directly recorded in conscious animals for 60 min. Square pulses (1 ms, 3 V, 30 Hz) were applied intermittently (20/20 s ON/OFF) to the CS for 48 h. After the end of stimulation, AP was recorded again. Nonstimulated rats (control group) and rats without electrodes around the CS (sham-operated) were also studied. Next, the animals were decapitated, and segments of mesenteric resistance arteries were removed to study vascular function. After the stimulation period, AP was 16 ± 5 mmHg lower in the stimulated group, whereas sham-operated and control rats showed similar AP between the first and second recording periods. Heart rate variability (HRV) evaluated using time and frequency domain tools and a nonlinear approach (symbolic analysis) suggested that hypertensive rats with electrodes around the CS, stimulated or not, exhibited a shift in cardiac sympathovagal balance towards parasympathetic tone. The relaxation response to acetylcholine in endothelium-intact mesenteric arteries was enhanced in rats that underwent CS stimulation for 48 h. In conclusion, long-term CS stimulation is effective in reducing AP levels, improving HRV and increasing mesenteric vascular relaxation in l-NAME hypertensive rats. Moreover, only the presence of electrodes around the CS is effective in eliciting changes in HRV similar to those observed in stimulated rats.

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

Similar content being viewed by others

References

  1. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol. 2011;58:765–73.

    Article  PubMed  Google Scholar 

  2. Lohmeier TE, Iliescu R. Chronic lowering of blood pressure by carotid baroreflex activation: mechanisms and potential for hypertension therapy. Hypertension. 2011;57:880–6.

    Article  CAS  PubMed  Google Scholar 

  3. Hoppe UC, Brandt MC, Wachter R, Beige J, Rump LC, Kroon AA, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens. 2012;6:270–6.

    Article  PubMed  Google Scholar 

  4. Georgakopoulos D, Little WC, Abraham WT, Weaver FA, Zile MR. Chronic baroreflex activation: a potential therapeutic approach to heart failure with preserved ejection fraction. J Card Fail. 2011;17:167–78.

    Article  PubMed  Google Scholar 

  5. Zannad F, Stough WG, Mahfoud F, Bakris GL, Kjeldsen SE, Kieval RS, et al. Design considerations for clinical trials of autonomic modulation therapies targeting hypertension and heart failure. Hypertension. 2015;65:5–15.

    Article  CAS  PubMed  Google Scholar 

  6. Courand P-Y, Feugier P, Workineh S, Harbaoui B, Bricca G, Lantelme P. Baroreceptor stimulation for resistant hypertension: first implantation in France and literature review. Arch Cardiovasc Dis. 2014;107:690–6.

    Article  PubMed  Google Scholar 

  7. Griffith LS, Schwartz SI. Reversal of renal hypertension by electrical stimulation of the carotid sinus nerve. Surgery. 1964;56:232–9.

    CAS  PubMed  Google Scholar 

  8. Navaneethan SD, Lohmeier TE, Bisognano JD. Baroreflex stimulation: a novel treatment option for resistant hypertension. J Am Soc Hypertens. 2009;3:69–74.

    Article  PubMed  Google Scholar 

  9. Lohmeier TE, Irwin ED, Rossing MA, Serdar DJ, Kieval RS. Prolonged activation of the baroreflex produces sustained hypotension. Hypertension. 2004;43:306–11.

    Article  CAS  PubMed  Google Scholar 

  10. Lohmeier TE, Barrett AM, Irwin ED. Prolonged activation of the baroreflex: a viable approach for the treatment of hypertension? Curr Hypertens Rep. 2005;7:193–8.

    Article  PubMed  Google Scholar 

  11. Lohmeier TE, Hildebrandt DA, Dwyer TM, Barrett AM, Irwin ED, Rossing MA, et al. Renal denervation does not abolish sustained baroreflex-mediated reductions in arterial pressure. Hypertension. 2007;49:373–9.

    Article  CAS  PubMed  Google Scholar 

  12. Parsonnet V, Rothfeld EL, Raman KV, Myers GH. Electrical stimulation of the carotid sinus nerve. Surg Clin North Am. 1969;49:589–96.

    Article  CAS  PubMed  Google Scholar 

  13. Illig KA, Levy M, Sanchez L, Trachiotis GD, Shanley C, Irwin E, et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg. 2006;44:1213–8.

    Article  PubMed  Google Scholar 

  14. Filippone JD, Bisognano JD. Baroreflex stimulation in the treatment of hypertension. Curr Opin Nephrol Hypertens. 2007;16:403–8.

    Article  PubMed  Google Scholar 

  15. Scheffers IJ, Kroon AA, Schmidli J, Jordan J, Tordoir JJ, Mohaupt MG, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol. 2010;56:1254–8.

    Article  PubMed  Google Scholar 

  16. Gassler JP, Lynch PS, Bisognano JD. The role of baroreflex activation therapy in sympathetic modulation for the treatment of resistant hypertension. Heart. 2012;98:1689–92.

    Article  PubMed  Google Scholar 

  17. Alnima T, de Leeuw PW, Tan FE, Kroon AA. Rheos Pivotal Trial, Investigators. Renal responses to long-term carotid baroreflex activation therapy in patients with drug-resistant hypertension. Hypertension. 2013;61:1334–9.

  18. Su D-F, Miao C-Y. Reduction of blood pressure variability: a new strategy for the treatment of hypertension. Trends Pharm Sci. 2005;26:388–90.

    Article  CAS  PubMed  Google Scholar 

  19. Thayer JF, Lane RD. The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychol. 2007;74:224–42.

    Article  PubMed  Google Scholar 

  20. Katayama PL, Castania JA, Dias DP, Patel KP, Fazan R Jr, Salgado HC. Role of chemoreceptor activation in hemodynamic responses to electrical stimulation of the carotid sinus in conscious rats. Hypertension. 2015;66:598–603.

    Article  CAS  PubMed  Google Scholar 

  21. Santos-Almeida FM, Domingos-Souza G, Meschiari CA, Favaro LC, Becari C, Castania JA, et al. Carotid sinus nerve electrical stimulation in conscious rats attenuates systemic inflammation via chemoreceptor activation. Sci Rep. 2017;7:6265.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R. Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension. 1992;20:298–303.

    Article  CAS  PubMed  Google Scholar 

  23. Zatz R, Baylis C. Chronic nitric oxide inhibition model six years on. Hypertension. 1998;32:958–64.

    Article  CAS  PubMed  Google Scholar 

  24. Dos Santos FM, Martins Dias DP, da Silva CA, Fazan R Jr, Salgado HC. Sympathetic activity is not increased in L-NAME hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2010;298:R89–95.

    Article  PubMed  CAS  Google Scholar 

  25. Scrogin KE, Veelken R, Luft FC. Sympathetic baroreceptor responses after chronic NG-nitro-L-arginine methyl ester treatment in conscious rats. Hypertension. 1994;23:982–6.

    Article  CAS  PubMed  Google Scholar 

  26. Qadri F, Carretero OA, Scicli AG. Centrally produced neuronal nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and spontaneously hypertensive rats. Jpn J Pharm. 1999;81:279–85.

    Article  CAS  Google Scholar 

  27. Margatho LO, Porcari CY, Macchione AF, da Silva Souza GD, Caeiro XE, Antunes-Rodrigues J, et al. Temporal dissociation between sodium depletion and sodium appetite appearance: involvement of inhibitory and stimulatory signals. Neuroscience. 2015;297:78–88.

    Article  CAS  PubMed  Google Scholar 

  28. Domingos-Souza G, Meschiari CA, Buzelle SL, Callera JC, Antunes-Rodrigues J. Sodium and water intake are not affected by GABAC receptor activation in the lateral parabrachial nucleus of sodium-depleted rats. J Chem Neuroanat. 2016;74:47–54.

    Article  CAS  PubMed  Google Scholar 

  29. Duque JJ, Silva LE, Murta LO. Open architecture software platform for biomedical signal analysis. Conf Proc IEEE Eng Med Biol Soc. 2013;2013:2084–7.

    Google Scholar 

  30. Montano N, Ruscone TG, Porta A, Lombardi F, Pagani M, Malliani A. Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt. Circulation. 1994;90:1826–31.

    Article  CAS  PubMed  Google Scholar 

  31. Porta A, Guzzetti S, Montano N, Furlan R, Pagani M, Malliani A, et al. Entropy, entropy rate, and pattern classification as tools to typify complexity in short heart period variability series. IEEE Trans Biomed Eng. 2001;48:1282–91.

    Article  CAS  PubMed  Google Scholar 

  32. Guzzetti. Symbolic dynamics of heart rate variability: a probe to investigate cardiac autonomic modulation (vol 112, pg 465, 2005). Circulation. 2005;112:E122–E122.

    Article  Google Scholar 

  33. Kollai M, Koizumi K. Reciprocal and non-reciprocal action of the vagal and sympathetic nerves innervating the heart. J Auton Nerv Syst. 1979;1:33–52.

    Article  CAS  PubMed  Google Scholar 

  34. Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.

    Article  CAS  PubMed  Google Scholar 

  35. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, et al. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995;91:1314–9.

    Article  CAS  PubMed  Google Scholar 

  36. da Silva CG, Specht A, Wegiel B, Ferran C, Kaczmarek E. Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells. Circulation. 2009;119:871–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Lohmeier TE, Iliescu R, Dwyer TM, Irwin ED, Cates AW, Rossing MA. Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol. 2010;299:H402–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hildebrandt DA, Irwin ED, Cates AW, Lohmeier TE. Regulation of renin secretion and arterial pressure during prolonged baroreflex activation: influence of salt intake. Hypertension. 2014;64:604–9.

    Article  CAS  PubMed  Google Scholar 

  39. Wustmann K, Kucera JP, Scheffers I, Mohaupt M, Kroon AA, de Leeuw PW, et al. Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension. Hypertension. 2009;54:530–6.

    Article  CAS  PubMed  Google Scholar 

  40. Castania JA, Katayama PL, Brognara F, Moraes DJA, Sabino JPJ, Salgado HC. Selective denervation of the aortic and carotid baroreceptors in rats. Exp Physiol. 2019;104:1335–42.

    Article  CAS  PubMed  Google Scholar 

  41. Bloch MJ, Basile JN. The Rheos Pivotol trial evaluating baroreflex activation therapy fails to meet efficacy and safety end points in resistant hypertension: back to the drawing board. J Clin Hypertens. 2012;14:184–6.

    Article  Google Scholar 

  42. Heusser K, Tank J, Luft FC, Jordan J. Baroreflex failure. Hypertension. 2005;45:834–9.

    Article  CAS  PubMed  Google Scholar 

  43. Porta A, Tobaldini E, Guzzetti S, Furlan R, Montano N, Gnecchi-Ruscone T. Assessment of cardiac autonomic modulation during graded head-up tilt by symbolic analysis of heart rate variability. Am J Physiol-Heart Circulatory Physiol. 2007;293:H702–8.

    Article  CAS  Google Scholar 

  44. Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010;55:619–26.

    Article  CAS  PubMed  Google Scholar 

  45. Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res. 2014;114:1804–14.

    Article  CAS  PubMed  Google Scholar 

  46. Tucker DC, Johnson AK. Development of autonomic control of heart rate in genetically hypertensive and normotensive rats. Am J Physiol. 1984;246:R570–7.

    CAS  PubMed  Google Scholar 

  47. McCarty R, Kirby RF, Cierpial MA, Jenal TJ. Accelerated development of cardiac sympathetic responses in spontaneously hypertensive (SHR) rats. Behav Neural Biol. 1987;48:321–33.

    Article  CAS  PubMed  Google Scholar 

  48. Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, et al. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007;35:2762–8.

    PubMed  Google Scholar 

  49. Gierthmuehlen M, Plachta DT. Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication. Hypertens Res. 2016;39:79–87.

    Article  CAS  PubMed  Google Scholar 

  50. Kang K-T. Endothelium-derived relaxing factors of small resistance arteries in hypertension. Toxicological Res. 2014;30:141–8.

    Article  CAS  Google Scholar 

  51. Paulis L, Zicha J, Kunes J, Hojna S, Behuliak M, Celec P, et al. Regression of L-NAME-induced hypertension: the role of nitric oxide and endothelium-derived constricting factor. Hypertens Res. 2008;31:793–803.

    Article  CAS  PubMed  Google Scholar 

  52. Jiang J, Zheng J-P, Li Y, Gan Z, Jiang Y, Huang D, et al. Differential contribution of endothelium-derived relaxing factors to vascular reactivity in conduit and resistance arteries from normotensive and hypertensive rats. Clin Exp Hypertens. 2016;38:393–8.

    Article  CAS  PubMed  Google Scholar 

  53. Garland CJ, Hiley CR, Dora KA. EDHF: spreading the influence of the endothelium. Br J Pharm. 2011;164:839–52.

    Article  CAS  Google Scholar 

  54. Iwama Y, Kato T, Muramatsu M, Asano H, Shimizu K, Toki Y, et al. Correlation with blood pressure of the acetylcholine-induced endothelium-derived contracting factor in the rat aorta. Hypertension. 1992;19:326–32.

    Article  CAS  PubMed  Google Scholar 

  55. Gardiner SM, Compton AM, Bennett T, Palmer RM, Moncada S. Control of regional blood flow by endothelium-derived nitric oxide. Hypertension. 1990;15:486–92.

    Article  CAS  PubMed  Google Scholar 

  56. Sander M, Hansen J, Victor RG. The sympathetic nervous system is involved in the maintenance but not initiation of the hypertension induced by N(omega)-nitro-L-arginine methyl ester. Hypertension. 1997;30:64–70.

    Article  CAS  PubMed  Google Scholar 

  57. Biancardi VC, Bergamaschi CT, Lopes OU, Campos RR. Sympathetic activation in rats with L-NAME-induced hypertension. Braz J Med Biol Res. 2007;40:401–8.

    Article  CAS  PubMed  Google Scholar 

  58. Rees DD, Palmer RM, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharm. 1990;101:746–52.

    Article  CAS  Google Scholar 

  59. Wilson C, Lee MD, McCarron JG. Acetylcholine released by endothelial cells facilitates flow-mediated dilatation. J Physiol. 2016;594:7267–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ghosh S, Gupta M, Xu W, Mavrakis DA, Janocha AJ, Comhair SA, et al. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2016;310:L1199–205.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Harris MB, Ju H, Venema VJ, Liang H, Zou R, Michell BJ, et al. Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem. 2001;276:16587–91.

    Article  CAS  PubMed  Google Scholar 

  62. Chen CA, Druhan LJ, Varadharaj S, Chen YR, Zweier JL. Phosphorylation of endothelial nitric-oxide synthase regulates superoxide generation from the enzyme. J Biol Chem. 2008;283:27038–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen F, Kumar S, Yu Y, Aggarwal S, Gross C, Wang Y, et al. PKC-dependent phosphorylation of eNOS at T495 regulates eNOS coupling and endothelial barrier function in response to G+ -toxins. PLoS ONE. 2014;9:e99823.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Financial support

FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo).

Author information

Authors and Affiliations

  1. Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil

    Gean Domingos-Souza, Fernanda Machado Santos-Almeida, César Arruda Meschiari, Luiz Eduardo Virgílio Silva, Jaci Airton Castania & Rubens Fazan Jr

  2. Department of Biomedical Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211, USA

    Gean Domingos-Souza & Diana Martinez

  3. Health and Sports Science Center, Federal University of Acre, Rio Branco, AC, Brazil

    César Arruda Meschiari

  4. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil

    Nathanne S. Ferreira, Camila A. Pereira & Rita C. Tostes

  5. Barão de Mauá University Center, Ribeirão Preto, SP, Brazil

    Daniel Penteado Martins Dias

Authors
  1. Gean Domingos-Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fernanda Machado Santos-Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. César Arruda Meschiari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nathanne S. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Camila A. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Diana Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel Penteado Martins Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luiz Eduardo Virgílio Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jaci Airton Castania
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rita C. Tostes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rubens Fazan Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gean Domingos-Souza.

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

Domingos-Souza, G., Santos-Almeida, F.M., Meschiari, C.A. et al. Electrical stimulation of the carotid sinus lowers arterial pressure and improves heart rate variability in l-NAME hypertensive conscious rats. Hypertens Res 43, 1057–1067 (2020). https://doi.org/10.1038/s41440-020-0448-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-020-0448-7

Keywords

This article is cited by

Search

Advanced search

Quick links