Skip to main content
Log in

Low-level Chronic Lead Exposure Impairs Neural Control of Blood Pressure and Heart Rate in Rats

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Lead (Pb) induces adverse effects when it chronically accumulates in the body, including effects on the nervous and cardiovascular systems. Wistar rats were exposed to lead acetate for 30 days (first dose 4 µg/100 g followed by 0.05 µg/100 g/day, i.m.) to investigate the cardiovascular system impact on the autonomic control. The femoral artery and vein were catheterised to perform hemodynamic evaluations in awake rats: heart rate variability (HRV), baroreflex sensitivity, cardiopulmonary reflex and hemodynamic responses to vagal and sympathetic pharmacological blockade. Rats exposed to Pb exhibited a higher blood pressure and reduced HRV in the time domain when compared to the saline-injected group. Spectral analysis of the HRV in the frequency-domain showed an augmented low-frequency component of the spectrum. Methylatropine and atenolol administration suggest increased sympathetic tone and reduced vagal tone on the control of heart rate. Chronic Pb exposure decreased the sensitivity of the baroreflex without significantly changing the cardiopulmonary reflex. This study demonstrated for the first time in an animal model of a controlled, low-dose chronic lead exposure that cardiovascular changes, such as arterial hypertension, are accompanied by impaired autonomic control of the cardiovascular system, as characterised by reduced baroreflex sensitivity and a sympathovagal imbalance.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Patrick, L. (2006). Lead toxicity, a review of the literature. Part 1: Exposure, evaluation, and treatment. Alternative Medicine Review, 11(1), 2–22.

    PubMed  Google Scholar 

  2. Roncal, C., Mu, W., Reungjui, S., Kim, K. M., Henderson, G. N., Ouyang, X., et al. (2007). Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease. American Journal of Physiology. Renal Physiology, 293(4), F1391–F1396.

    Article  CAS  PubMed  Google Scholar 

  3. Fioresi, M., Simões, M. R., Furieri, L. B., Broseghini-Filho, G. B., Vescovi, M. V., Stefanon, I., & Vassallo, D. V. (2014). Chronic lead exposure increases blood pressure and myocardial contractility in rats. PLoS One, 9(5), e96900.

    Article  PubMed  PubMed Central  Google Scholar 

  4. ATSDR (Agency for Toxic Substances and Disease Registry). (2005). Toxicological profile for lead. Annual report. Atlanta: Department of Health and Human Services, Public Health Service.

  5. Den, H. E., Nawrot, T., & Staessen, J. A. (2002). The relationship between blood pressure and blood lead in NHANES III. National Health and Nutritional Examination Survey. Journal of Human Hypertension, 16, 563–568.

    Article  Google Scholar 

  6. Vupputuri, S., He, J., Muntner, P., Bazzano, L. A., Whelton, P. K., & Batuman, V. (2003). Blood lead level is associated with elevated blood pressure in blacks. Hypertension, 41, 463–468.

    Article  CAS  PubMed  Google Scholar 

  7. Silveira, E. A., Siman, F. D., de Oliveira Faria, T., Vescovi, M. V., Furieri, L. B., Lizardo, J. H., et al. (2014). Low-dose chronic lead exposure increases systolic arterial pressure and vascular reactivity of rat aortas. Free Radical Biology and Medicine, 67, 366–376.

    Article  CAS  PubMed  Google Scholar 

  8. Nunes, K. Z., Nunes, D. O., Silveira, E. A., Cruz Pereira, C. A., Broseghini Filho, G. B., Vassallo, D. V., & Fioresi, M. (2015). Chronic lead exposure decreases the vascular reactivity of rat aortas: the role of hydrogen peroxide. PLoS One, 10(3), e0120965.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Simões, M. R., Aguado, A., Fiorim, J., Silveira, E. A., Azevedo, B. F., Toscano, C. M., et al. (2015). MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways. Toxicology and Applied Pharmacology, 283(2), 127–138.

    Article  PubMed  Google Scholar 

  10. Gonick, H. C., Ding, Y., Bondy, S. C., Ni, Z., & Vaziri, N. D. (1997). Lead-induced hypertension: Interplay of nitric oxide and reactive oxygen species. Hypertension, 30(6), 1487–1492.

    Article  CAS  PubMed  Google Scholar 

  11. Khalil-Manesh, F., Gonick, H. C., Weiler, E. W., Prins, B., Weber, M. A., & Purdy, R. E. (1993). Lead-induced hypertension: Possible role of endothelial factors. American Journal of Hypertension, 6(9), 723–729.

    Article  CAS  PubMed  Google Scholar 

  12. Vaziri, N. D., Liang, K., & Ding, Y. (1999). Increased nitric oxide inactivation by reactive oxygen species in lead-induced hypertension. Kidney International, 56(4), 1492–1498.

    Article  CAS  PubMed  Google Scholar 

  13. Simões, M. R., Ribeiro Júnior, R. F., Vescovi, M. V., de Jesus, H. C., Padilha, A. S., Stefanon, I., et al. (2011). Acute lead exposure increases arterial pressure: Role of the renin-angiotensin system. PLoS One, 6(4), e18730.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tsao, D. A., Yu, H. S., Cheng, J. T., Ho, C. K., & Chang, H. R. (2000). The change of beta-adrenergic system in lead-induced hypertension. Toxicology and Applied Pharmacology, 164(2), 127–133.

    Article  CAS  PubMed  Google Scholar 

  15. Moreira, F. R., & Moreira, J. C. (2004). Effects of lead exposure on the human body and health implications. Revista Panamericana de Salud Pública, 15(2), 119–129.

    Article  PubMed  Google Scholar 

  16. Stewart, W. F., Schwartz, B. S., Simon, D., Kelsey, K., & Todd, A. C. (2002). ApoE genotype, past adult lead exposure, and neurobehavioral function. Environmental Health Perspectives, 110(5), 501–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Poręba, R., Poręba, M., Gać, P., Steinmetz-Beck, A., Beck, B., Pilecki, W., et al. (2011). Electrocardiographic changes in workers occupationally exposed to lead. Annals of Noninvasive Electrocardiology, 16(1), 33–40.

    Article  PubMed  Google Scholar 

  18. Jhun, H. J., Kim, H., & Paek, D. M. (2005). The association between blood metal concentrations and heart rate variability: A crosssectional study. International Archives of Occupational and Environmental Health, 78, 243–247.

    Article  CAS  PubMed  Google Scholar 

  19. Carmignani, M., Volpe, A. R., Boscolo, P., Qiao, N., Di Gioacchino, M., Grilli, A., & Felaco, M. (2000). Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective functional impairment. Life Sciences, 68(4), 401–415.

    Article  CAS  PubMed  Google Scholar 

  20. Vasquez, E. C., Meyrelles, S. S., Mauad, H., & Cabral, A. M. (1997). Neural reflex regulation of arterial pressure in pathophysiological conditions: Interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex. Brazilian Journal of Medical and Biological Research, 30(4), 521–532.

    Article  CAS  PubMed  Google Scholar 

  21. Peotta, V. A., Vasquez, E. C., & Meyrelles, S. S. (2001). Cardiovascular neural reflexes in L-NAME-induced hypertension in mice. Hypertension, 38, 555–559.

    Article  CAS  PubMed  Google Scholar 

  22. Lacerda, J. E., Consolim-Colombo, F. M., Moreira, E. D., Ida, F., Silva, G. J., Irigoyen, M. C., & Krieger, E. M. (2007). Influence of cardiopulmonary reflex on the sympathetic activity during myocardial infarction. Autonomic Neuroscience, 133(2), 128–135.

    Article  PubMed  Google Scholar 

  23. Lee, H. B., & Blaufox, M. D. (1985). Blood volume in the rat. Journal of Nuclear Medicine, 26(1), 72–76.

    CAS  PubMed  Google Scholar 

  24. Fiorim, J., Ribeiro Junior, R. F., Silveira, E. A., Padilha, A. S., Vescovi, M. V., de Jesus, H. C., et al. (2011). Low-level lead exposure increases systolic arterial pressure and endothelium-derived vasodilator factors in rat aortas. PLoS One, 6(2), e17117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oliveira, L. R., de Melo, V. U., Macedo, F. N., Barreto, A. S., Badaue-Passos, D, Jr., Viana dos Santos, M. R., et al. (2012). Induction of chronic non-inflammatory widespread pain increases cardiac sympathetic modulation in rats. Autonomic Neuroscience, 167, 45–49.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fazan, R, Jr., de Oliveira, M., Oliveira, J. A., Salgado, H. C., & Garcia-Cairasco, N. (2011). Changes in autonomic control of the cardiovascular system in the Wistar audiogenic rat (WAR) strain. Epilepsy & Behavior, 22, 666–670.

    Article  Google Scholar 

  27. Sharp, D. S., Becker, C. E., & Smith, A. H. (1987). Chronic low-level lead exposure. Its role in the pathogenesis of hypertension. Medical Toxicology, 2(3), 210–232.

    Article  CAS  PubMed  Google Scholar 

  28. Hertz-Picciotto, I., & Croft, J. (1993). Review of the relation between blood lead and blood pressure. Epidemiologic Reviews, 15(2), 352–373.

    Article  CAS  PubMed  Google Scholar 

  29. Silveira, E. A., Lizardo, J. H., Souza, L. P., Stefanon, I., & Vassallo, D. V. (2010). Acute lead-induced vasoconstriction in the vascular beds of isolated perfused rat tails is endothelium-dependent. Brazilian Journal of Medical and Biological Research, 43(5), 492–499.

    Article  CAS  PubMed  Google Scholar 

  30. Lai, C. C., Lin, H. H., Chen, C. W., Chen, S. H., & Chiu, T. H. (2002). Excitatory action of lead on rat sympathetic preganglionic neurons in vitro and in vivo. Life Sciences, 71(9), 1035–1045.

    Article  CAS  PubMed  Google Scholar 

  31. Chapleau, M. W., Li, Z., Meyrelles, S. S., Ma, X., & Abboud, F. M. (2001). Mechanisms determining sensitivity of baroreceptor afferents in health and disease. Annals of the New York Academy of Sciences, 940, 1–19.

    Article  CAS  PubMed  Google Scholar 

  32. Lanfranchi, P. A., & Somers, V. K. (2002). Arterial baroreflex function and cardiovascular variability: interactions and implications. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 283, R815–R826.

    Article  PubMed  Google Scholar 

  33. Weston, P. J., Panerai, R. B., McCullough, A., McNally, P. G., James, M. A., Potter, J. F., et al. (1996). Assessment of baroreceptor-cardiac reflex sensitivity using time domain analysis in patients with IDDM and the relation to left ventricular mass index. Diabetologia, 39, 1385–1391.

    Article  CAS  PubMed  Google Scholar 

  34. Parati, G., & Esler, M. (2012). The human sympathetic nervous system: Its relevance in hypertension and heart failure. European Heart Journal, 33, 1058–1066.

    Article  CAS  PubMed  Google Scholar 

  35. Cardoso, L. M., Fernandes, L. G., Alves, A. M., Pedrosa, M. L., Silva, M. E., Colombari, E., et al. (2007). Cardiopulmonary reflex is attenuated in iron overload conscious rats. Nutritional Neuroscience, 10(3–4), 121–128.

    Article  CAS  PubMed  Google Scholar 

  36. Carmignani, M., Finelli, V. N., & Boscolo, P. (1983). Mechanisms in cardiovascular regulation following chronic exposure of male rats to inorganic mercury. Toxicology and Applied Pharmacology, 69(3), 442–450.

    Article  CAS  PubMed  Google Scholar 

  37. Germanó, D., Pochiero, M., Romeo, G., Nunziata, A., Costa, G., & Caputi, A. P. (1984). Cadmium alters arterial baroreflex control of heart rate in the conscious rat. Archives of Toxicology, 7, 374–377.

    Article  PubMed  Google Scholar 

  38. Boscolo, P., & Carmignani, M. (1988). Neurohumoral blood pressure regulation in lead exposure. Environmental Health Perspectives, 78, 101–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Iannaccone, A., Boscolo, P., & Carmignani, M. (1981). Neurogenic and humoral mechanisms in arterial hypertension of chronically lead-exposed rats. Medicina del Lavoro, 72, 13–21.

    CAS  PubMed  Google Scholar 

  40. Carmignani, M., Boscolo, P., Marchetti, P., & Iannaccone, A. (1980). Neurogenic components in cardiovascular reactivity of chronically lead-exposed rats. Developments in Toxicology and Environmental Science, 8, 595–598.

    CAS  PubMed  Google Scholar 

  41. Casadei, B., & Paterson, D. J. (2000). Should we still use nitrovasodilators to test baroreflex sensitivity? Journal of Hypertension, 18(1), 3–6.

    Article  CAS  PubMed  Google Scholar 

  42. Sener, A., & Smith, F. G. (2001). Nitric oxide modulates arterial baroreflex control of heart rate in conscious lambs in an age-dependent manner. American Journal of Physiology Heart and Circulatory Physiology, 280(5), H2255–H2263.

    CAS  PubMed  Google Scholar 

  43. Schwarz, P., Diem, R., Dun, N. J., & Forstermann, U. (1995). Endogenous and exogenous nitric oxide inhibits norepinephrine release from rat heart sympathetic nerves. Circulation Research, 77, 841–848.

    Article  CAS  PubMed  Google Scholar 

  44. Reddy, G. R., Davi, B. C., & Chetty, C. S. (2007). Developmental lead neurotoxicity: Alterations in brain cholinergic system. Neurotoxicology, 28(2), 402–407.

    Article  CAS  PubMed  Google Scholar 

  45. Borisova, T., Krisanova, N., Sivko, R., Kasatkina, L., Borysov, A., Griffin, S., & Wireman, M. (2011). Presynaptic malfunction: The neurotoxic effects of cadmium and lead on the proton gradient of synaptic vesicles and glutamate transport. Neurochemistry International, 59(2), 272–279.

    Article  CAS  PubMed  Google Scholar 

  46. Averill, D. B., & Diz, D. I. (2000). Angiotensin peptides and the baroreflex control of sympathetic outflow: Pathways and mechanisms of the medulla oblongata. Brain Research Bulletin, 51(2), 119–128.

    Article  CAS  PubMed  Google Scholar 

  47. Phillips, M. I., & Sumners, C. (1998). Angiotensin II in central nervous system physiology. Regulatory Peptides, 78, 1–11.

    Article  CAS  PubMed  Google Scholar 

  48. Carmignani, M., Boscolo, P., Poma, A., & Volpe, A. R. (1999). Kininergic system and arterial HTN following chronic exposure to inorganic lead. Immunopharmacology, 44, 105–110.

    Article  CAS  PubMed  Google Scholar 

  49. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. (1996). Heart rate variability: Standards of measurement, physiologic interpretation and clinical use. Circulation, 93, 1043–1065.

    Article  Google Scholar 

  50. Malliani, A., Lombardi, F., & Pagani, M. (1994). Power spectrum analysis of heart rate variability: A tool to explore neural regulatory mechanisms. British Heart Journal, 71, 1–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Feng, W., He, X., Chen, M., Deng, S., Qiu, G., Li, X., et al. (2015). Urinary metals and heart rate variability: A cross-sectional study of urban adults in Wuhan. China. Environmental Health Perspectives, 123(3), 217–222.

    CAS  PubMed  Google Scholar 

  52. Böckelmann, I., Pfister, E., & Darius, S. (2011). Early effects of long-term neurotoxic lead exposure in copper works employees. Journal of Toxicology, 2011, 832519.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Moraes, O. A., Colucci, J. A., Souza, L. E., Scapini, K. B., Moraes-Silva, I. C., Mostarda, C., et al. (2013). Cardiovascular autonomic dysfunction in non-obese diabetic mice. Autonomic Neuroscience, 177, 143–147.

    Article  PubMed  Google Scholar 

  54. Presciuttini, B., Duprez, D., De Buyzere, M., & Clement, D. L. (1998). How to study sympatho-vagal balance in arterial hypertension and the effect of antihypertensive drugs? Acta Cardiologica, 53, 143–152.

    CAS  PubMed  Google Scholar 

  55. Kleiger, R. E., Stein, P. K., & Bigger, J. T, Jr. (2005). Heart rate variability: Measurement and clinical utility. Annals of Noninvasive Electrocardiology, 10, 88–101.

    Article  PubMed  Google Scholar 

  56. Cabral, A. M., & Vasquez, E. C. (1991). Time course of cardiac sympathetic and vagal tone changes in renovascular hypertensive rats. American Journal of Hypertension, 4, 815–819.

    Article  CAS  PubMed  Google Scholar 

  57. Wang, J., Wu, J., & Zhang, Z. (2006). Oxidative stress in mouse brain exposed to lead. The Annals of occupational hygiene, 50(4), 405–409.

    CAS  PubMed  Google Scholar 

  58. Shin, C. Y., Choi, J. W., Choi, M. S., Ryu, J. R., Ko, K. H., & Cheong, J. H. (2007). Developmental changes of the activity of monoamine oxidase in pre- and postnatally lead exposed rats. Environmental Toxicology and Pharmacology, 24(1), 5–10.

    Article  CAS  PubMed  Google Scholar 

  59. Xu, J., Yan, C. H., Yang, B., Xie, H. F., Zou, X. Y., Zhong, L., et al. (2009). The role of metabotropic glutamate receptor 5 in developmental lead neurotoxicity. Toxicology Letters, 191(2–3), 223–230.

    Article  CAS  PubMed  Google Scholar 

  60. Guimarães, D., Santos, J. P., Carvalho, M. L., Diniz, M. S., House, B., & Miller, V. M. (2014). Analytical evidence of heterogeneous lead accumulation in the hypothalamic defence area and nucleus tractus solitarius. Neurotoxicology, 44, 91–97.

    Article  PubMed  Google Scholar 

  61. Lin, L. H., Moore, S. A., Jones, S. Y., McGlashon, J., & Talman, W. T. (2013). Astrocytes in the rat nucleus tractus solitarii are critical for cardiovascular reflex control. The Journal of Neuroscience, 33(47), 18608–18617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Botelho-Ono, M. S., Pina, H. V., Sousa, K. H., Nunes, F. C., Medeiros, I. A., & Braga, V. A. (2011). Acute superoxide scavenging restores depressed baroreflex sensitivity in renovascular hypertensive rats. Autonomic Neuroscience, 159(1–2), 38–44.

    Article  CAS  PubMed  Google Scholar 

  63. Prentice, R. C., & Kopp, S. J. (1985). Cardiotoxicity of lead at various perfusate calcium concentrations: Functional and metabolic responses of the perfused rat heart. Toxicology and Applied Pharmacology, 81, 491–501.

    Article  CAS  PubMed  Google Scholar 

  64. Fioresi, M., Furieri, L. B., Simões, M. R., Ribeiro, R. F, Jr., Meira, E. F., Fernandes, A. A., et al. (2013). Acute exposure to lead increases myocardial contractility independent of hypertension development. Brazilian Journal of Medical and Biological Research, 46(2), 178–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vassallo, D. V., Lebarch, E. C., Moreira, C. M., Wiggers, G. A., & Stefanon, I. (2008). Lead reduces tension development and the myosin ATPase activity of the rat right ventricular myocardium. Brazilian Journal of Medical and Biological Research, 41(9), 789–795.

    Article  CAS  PubMed  Google Scholar 

  66. Monfredi, O., Maltsev, V. A., & Lakatta, E. G. (2013). Modern concepts concerning the origin of the heartbeat. Physiology, 28, 74–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Scott, B., & Lew, J. (1985). Chronic exposure to lead causes persistent alterations in the electric membrane properties of neurons in cell culture. Journal of Neurobiology, 16(6), 425–433.

    Article  CAS  PubMed  Google Scholar 

  68. Szücs, A., Salánki, J., & Rózsa, K. S. (1994). Effects of chronic exposure to cadmium- or lead-enriched environments on ionic currents of identified neurons in Lymnaea stagnalis L. Cellular and Molecular Neurobiology, 14(6), 769–780.

    Article  PubMed  Google Scholar 

  69. Fiorim, J., Ribeiro, R. F, Jr., Azevedo, B. F., Simões, M. R., Padilha, A. S., Stefanon, I., et al. (2012). Activation of K+ channels and Na+/K+ ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats. Toxicology and Applied Pharmacology, 262(1), 22–31.

    Article  CAS  PubMed  Google Scholar 

  70. Kempe, D. S., Lang, P. A., Eisele, K., Klarl, B. A., Wieder, T., Huber, S. M., et al. (2005). Stimulation of erythrocyte phosphatidylserine exposure by lead ions. American Journal of Physiology. Cell Physiology, 288(2), C396–C402.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was sponsored by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 441881/2014-9 and 301608/2011-3) and Fundação de Amparo à Pesquisa do Espírito Santo (PRONEX-FAPES/CNPq) in Brazil.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maylla Ronacher Simões.

Ethics declarations

Conflict of interest

None declared.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Simões, M.R., Preti, S.C., Azevedo, B.F. et al. Low-level Chronic Lead Exposure Impairs Neural Control of Blood Pressure and Heart Rate in Rats. Cardiovasc Toxicol 17, 190–199 (2017). https://doi.org/10.1007/s12012-016-9374-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-016-9374-y

Keywords

Navigation