Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cardiovascular Toxicology
Published in: Cardiovascular Toxicology 3/2020

01-06-2020 | Hypertension

Chronic Mercury Exposure in Prehypertensive SHRs Accelerates Hypertension Development and Activates Vasoprotective Mechanisms by Increasing NO and H2O2 Production

Authors: P. B. A. Fardin, R. P. Simões, I. R. G. Schereider, C. C. P. Almenara, M. R. Simões, D. V. Vassallo

Published in: Cardiovascular Toxicology | Issue 3/2020

Login to get access

Abstract

Mercury is a heavy metal associated with cardiovascular diseases. Studies have reported increased vascular reactivity without changes in systolic blood pressure (SBP) after chronic mercury chloride (HgCl2) exposure, an inorganic form of the metal, in normotensive rats. However, we do not know whether individuals in the prehypertensive phase, such as young spontaneously hypertensive rats (SHRs), are susceptible to increased arterial blood pressure. We investigated whether chronic HgCl2 exposure in young SHRs accelerates hypertension development by studying the vascular function of mesenteric resistance arteries (MRAs) and SBP in young SHRs during the prehypertensive phase. Four-week-old male SHRs were divided into two groups: the SHR control group (vehicle) and the SHR HgCl2 group (4 weeks of exposure). The results showed that HgCl2 treatment accelerated the development of hypertension; reduced vascular reactivity to phenylephrine in MRAs; increased nitric oxide (NO) generation; promoted vascular dysfunction by increasing the production of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2); increased Gp91Phox protein levels and in situ levels of superoxide anion (O 2 ·− ); and reduced vasoconstrictor prostanoid production compared to vehicle treatment. Although HgCl2 accelerated the development of hypertension, the HgCl2-exposed animals also exhibited a vasoprotective mechanism to counterbalance the rapid increase in SBP by decreasing vascular reactivity through H2O2 and NO overproduction. Our results suggest that HgCl2 exposure potentiates this vasoprotective mechanism against the early establishment of hypertension. Therefore, we are concluding that chronic exposure to HgCl2 in prehypertensive animals could enhance the risk for cardiovascular diseases.
Literature
1.
Langworth, S. (1997). Exposure to mercury vapor and impact on health in the dental profession in Sweden. Journal of Dental Research,76(7), 1397–1404.PubMed
2.
Salonen, J. T., Seppänen, K., Lakka, T. A., Salonen, R., & Kaplan, G. A. (2000). Mercury accumulation and accelerated progression of carotid atherosclerosis: A population-based prospective 4-year follow-up study in men in eastern Finland. Atherosclerosis,148(2), 265–273.PubMed
3.
Clarkson, T. W., Magos, L., & Myers, G. J. (2003). The toxicology of mercury—Current exposures and clinical manifestations. New England Journal of Medicine,349(18), 1731–1737.PubMed
4.
McKelvey, W., Gwynn, R. C., Jeffery, N., Kass, D., Garg, R. K., Thorpe, L. E., et al. (2007). A biomonitoring study of lead, cadmium, and mercury in the blood of New York city adults. Environmental Health Perspectives,115(10), 1435–1441.PubMedCentralPubMed
5.
Virtanen, J. K., Rissanen, T. H., Voutilainen, S., & Tuomainen, T. P. (2007). Mercury as a risk factor for cardiovascular diseases. Journal of Nutritional Biochemistry,18(2), 75–85.PubMed
6.
7.
Virtanen, J. K., Voutilainen, S., Rissanen, T. H., Mursu, J., Tuomainen, T. P., Korhonen, M. J., et al. (2005). Mercury, fish oils, and risk of acute coronary events and cardiovascular disease, coronary heart disease, and all-cause mortality in men in Eastern Finland. Arteriosclerosis, Thrombosis, and Vascular Biology,25(1), 228–233.PubMed
8.
Clarkson, T. W., Vyas, J. B., & Ballatori, N. (2007). Mechanisms of mercury disposition in body. American Journal of Industrial Medicine,50(10), 757–764.PubMed
9.
Salonen, J. T., Seppänen, K., Nyyssönen, K., Korpela, H., Kauhanen, J., Kantola, M., et al. (1995). Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in Eastern Finnish men. Circulation,91(3), 645–655.PubMed
10.
Clarkson, T. W. (1972). The biological properties and distribution of mercury. Biochemical Journal,130(2), 61–63.
11.
Zalups, R. K., & Lash, L. H. (1994). Invited review: Advances in understanding the renal transport and toxicity of mercury. Journal of Toxicology and Environment Health,42(1), 01–44.
12.
13.
Kishimoto, T., Oguri, T., & Tada, M. (1995). Effect of methylmercury (CH3HgCl) injury on nitric oxide synthase (NOS) activity in cultured human umbilical vascular endothelial cells. Toxicology,103(1), 1–7.PubMed
14.
Kishimoto, T., Oguri, T., Abe, M., Kajitani, H., & Tada, M. (1995). Inhibitory effect of methylmercury on migration and tube formation by cultured human vascular endothelial cells. Archives of Toxicology,69(6), 357–361.PubMed
15.
Weinsberg, F., Bickmeyer, U., & Wiegand, H. (1995). Effects of inorganic mercury (Hg2 +) on calcium channel currents and catecholamine release from bovine chromaffin cells. Archives of Toxicology,69(3), 191–196.PubMed
16.
Lim, H. E., Shim, J. J., Lee, S. Y., Lee, S. H., Kang, S. Y., Jo, J. Y., et al. (1998). Mercury inhalation poisoning and acute lung injury. Korean Journal of Internal Medicine,13(2), 127–130.PubMedPubMedCentral
17.
Boffetta, P., Sallsten, G., & Garcia-Gomez, M. (2001). Mortality from cardiovascular diseases and exposure to inorganic mercury. Occupational and Environmental Medicine,58, 461–466.PubMedCentralPubMed
18.
Omanwar, S., Ravi, K., & Fahim, M. (2011). Persistence of EDHF pathway and impairment of the nitric oxide pathway after chronic mercury chloride exposure in rats: Mechanisms of endothelial dysfunction. Human and Experimental Toxicology,30(11), 1777–1784.PubMed
19.
Houston, M. C. (2011). Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. Journal of Clinical Hypertension (Greenwich),13(8), 621–627.
20.
Lemos, N. B., Angeli, J. K., Faria, T. O., Ribeiro Junior, R. F., Vassallo, D. V., Padilha, A. S., et al. (2012). Low mercury concentration produces vasoconstriction, decreases nitric oxide bioavailability and increases oxidative stress in rat conductance artery. PLoS ONE,7(11), e49005.PubMedCentralPubMed
21.
Furieri, L. B., Galán, M., Avendaño, M. S., García-Redondo, A. B., Aguado, A., Martínez, S., et al. (2011). Endothelial dysfunction of rat coronary arteries after exposure to low concentrations of mercury is dependent on reactive oxygen species. British Journal of Pharmacology,162(8), 1819–1831.PubMedCentralPubMed
22.
Wiggers, G. A., Peçanha, F. M., Briones, A. M., Pérez-Girón, J. V., Miguel, M., Vassallo, D. V., et al. (2008). Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries. American Journal of Physiology-Heart and Circulatory Physiology,295(3), 1033–1043.
23.
Félétou, M., & Vanhoutte, P. M. (2006). Endothelial dysfunction: A multifaceted disorder (The Wiggers Award Lecture). American Journal of Physiology-Heart and Circulatory Physiology,291(3), 985–1002.
24.
Pecanha, F. M., Wiggers, G. A., Briones, A. M., Perez-Giron, J. V., Miguel, M., Garcia-Redondo, A. B., et al. (2010). The role of cyclooxygenase (COX)-2 derived prostanoids on vasoconstrictor responses to phenylephrine is increased by exposure to low mercury concentration. Journal of Physiology and Pharmacology,61(1), 29–36.PubMed
25.
Rizzetti, D. A., Torres, J. G., Escobar, A. G., Peçanha, F. M., Santos, F. W., Puntel, R. L., et al. (2013). Apocynin prevents vascular effects caused by chronic exposure to low concentrations of mercury. PLoS ONE,8(2), e55806.PubMedCentralPubMed
26.
27.
28.
Wiggers, G. A., Stefanon, I., Padilha, A. S., Peçanha, F. M., Vassallo, D. V., & Oliveira, E. M. (2008). Low nanomolar concentration of mercury chloride increases vascular reactivity to phenylephrine and local angiotensin production in rats. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology,147(2), 252–260.
29.
Grizzo, L. T., & Cordellini, S. (2008). Perinatal lead exposure affects nitric oxide and cyclooxygenase pathways in aorta of weaned rats. Toxicological Sciences,103(1), 207–214.PubMed
30.
Ribeiro Júnior, R. F., Pavan, B. M., Fiorim, J., Simoes, M. R., Dias, F. M., Lima, F. L., et al. (2012). Myocardial contractile dysfunction induced by ovariectomy requires AT 1 receptor activation in female rats. Cellular Physiology and Biochemistry,30(1), 1–12.
31.
32.
Vassallo, D. V., Simões, M. R., Furieri, L. B., Fioresi, M., Fiorim, J., & Almeida, E. A. S. (2011). Toxic effects of mercury, lead and gadolinium on vascular reactivity. Brazilian Journal of Medical and Biological Research,44(9), 939–946.PubMed
33.
Vassallo, D. V., Azevedo, B. F., Giuberti, K., Simões, M. R., Ribeiro Junior, R. F., & Salaices, M. (2018). Effects of chronic exposure to mercury on angiotensin-converting enzyme activity and oxidative stress in normotensive and hypertensive rats. Arquivos Brasileiros de Cardiologia,112, 1–7.
34.
Bristow, M. R. (1999). Mechanisms of development of heart failuve in the hypertensive patient. Cardiology,92, 3–6.PubMed
35.
36.
Arribas, S., Gordon, J., Daly, C. J., Dominiczak, A. F., & McGrath, J. C. (1996). Confocal microscopic characterization of a lesion in cerebral vessel of the stroke-prone spontaneously hypertensive rat. Stroke,27, 1118–1123.PubMed
37.
Mizutani, K., Ikeda, K., Kawai, Y., & Yamori, Y. (1999). Biomechanical properties and chemical composition of the aorta in genetic hypertensive rats. Journal of Hypertension,17, 481–487.PubMed
38.
Török, J., Koprdová, R., Cebová, M., Kuneš, J., & Kristek, F. (2006). Functional and structural pattern of arterial responses in hereditary hypertriglyceridemic and spontaneously hypertensive rats in early stage of experimental hypertension. Physiological Research,55, 65–71.
39.
Tsuda, K., Kuchii, M., Nishio, I., & Masuyama, Y. (1987). Presynaptic α2-adrenoceptor mediated regulation of norepinephrine release in perfused mesenteric vasculatures in young and adult spontaneously hypertensive rats. Japanese Circulation Journal,51, 25–32.PubMed
40.
Szemeredi, K., Bagdy, G., Stull, R., Keiser, H. R., Kopin, I. J., & Goldstein, D. S. (1988). Sympathoadrenomedullary hyper-responsiveness to yohimbine in juvenile spontaneously hypertensive rats. Life Sciences,43(13), 1063–1068.PubMed
41.
Zhao, Y., Vanhoutte, P. M., & Leung, S. W. S. (2012). Endothelial nitric oxide synthase-independent release of nitric oxide in the aorta of the spontaneously hypertensive rat. Journal of Pharmacology and Experimental Therapeutics,344(1), 15–22.PubMed
42.
Ibarra, M., López-Guerrero, J. J., Mejía-Zepeda, R., & Villalobos-Molina, R. (2006). Endothelium-dependent inhibition of the contractile response is decreased in aorta from aged and spontaneously hypertensive rats. Archives of Medical Research,37(3), 334–341.PubMed
43.
Cacanyiova, S., Berenyiova, A., Kristek, F., Drobna, M., Ondrias, K., & Grman, M. (2016). The adaptive role of nitric oxide and hydrogen sulphide in vasoactive responses of thoracic aorta is triggered already in young spontaneously hypertensive rats. Journal of Physiology and Pharmacology,67, 501–512.PubMed
44.
Wu, C. C., Hong, H. J., Chou, T. C., Ding, Y. A., & Yen, M. H. (1996). Evidence for inducible nitric oxide synthase in spontaneously hypertensive rats. Biochemical and Biophysical Research Communications,466, 459–466.
45.
Chou, T. C., Yen, M. H., Li, C. Y., & Ding, Y. A. (1998). Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension,31(2), 643–648.PubMed
46.
Vaziri, N. D., Ni, Z., & Oveisi, F. (1998). Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension,31(6), 1248–1254.PubMed
47.
Briones, A. M., Alonso, M. J., Marin, J., & Salaices, M. (1999). Role of iNOS in the vasodilator responses induced by l-arginine in the middle cerebral artery from normotensive and hypertensive rats. British Journal of Pharmacology,126(1), 111–120.PubMedCentralPubMed
48.
Briones, A. M., Balfagón, G., Marín, J., Alonso, M. J., & Salaices, M. (2000). Influence of hypertension on nitric oxide synthase expression and vascular effects of lipopolysaccharide in rat mesenteric arteries. British Journal of Pharmacology,131(2), 185–194.PubMedCentralPubMed
49.
Förstermann, U., Closs, E. I., Pollock, J. S., Nakane, M., Schwarz, P., Gath, I., et al. (1994). Nitric oxide synthase isozymes. Hypertension,23, 1121–1131.PubMed
50.
Förstemann, U., Nakane, M., Tracey, W. R., & Pollock, J. (1993). Isorfoms of nitric oxide syntase: Functions in the cardiovascular system. European Heart Journal,14, 10–15.
51.
Faria, T. O., Simões, M. R., Vassallo, D. V., Forechi, L., Almenara, C. C. P., Marchezini, B. A., et al. (2018). Xanthine oxidase activation modulates the endothelial (vascular) dysfunction related to HgCl2 exposure plus myocardial infarction in rats. Cardiovascular Toxicology,18(2), 161–174.PubMed
52.
Azevedo, B. F., Simões, M. R., Fiorim, J., Botelho, T., Angeli, J. K., Vieira, J., et al. (2016). Chronic mercury exposure at different concentrations produces opposed vascular responses in rat aorta. Clinical and Experimental Pharmacology and Physiology,43(7), 712–719.PubMed
53.
Hayabuchi, Y., Mori, K., Nakaya, Y., Sakamoto, S., Matsuoka, S., & Kuroda, Y. (1998). Lactate-induced vascular relaxation in porcine coronary arteries is mediated by Ca2 + -activated K + channels. Journal of Molecular and Cellular Cardiology,30(2), 349–356.PubMed
54.
Gil-Longo, J., & González-Vázquez, C. (2005). Characterization of four different effects elicited by H2O2 in rat aorta. Vascular Pharmacology,43(2), 128–138.PubMed
55.
Félétou, M. (2009). Calcium-activated potassium channels and endothelial dysfunction: Therapeutic options? British Journal of Pharmacology,156(4), 545–562.PubMedCentralPubMed
56.
Ferreira, A. L. A., & Matsubara, L. S. (1997). Radicais livres: Conceitos E Mecanismo De Lesão. Revista da Associacao Medica Brasileira Impact,43(1), 61–69.
57.
Zalba, G., Beaumont, F. J., José, G. S., Fortuño, M. A., Fortuño, A., Etayo, J. C., et al. (2012). Vascular NADH/NADPH oxidase is involved in enhanced superoxide production in spontaneously hypertensive rats. Hypertension,35(5), 1055–1061.
58.
Gongora, M. C., Laude, K., Folz, J. R., Kim, H. W., McCann, L., Qin, Z., et al. (2006). Role of extracellular superoxide dismutase in hypertension. Hypertension,48(3), 473–481.PubMed
59.
Urakami-Harasawa, L., Shimokawa, H., Nakashima, M., Egashira, K., & Takeshita, A. (1997). Importance of endothelium-derived hyperpolarizing factor in human arteries. Journal of Clinical Investigation,100(11), 2793–2799.PubMedCentralPubMed
60.
Alvarez, Y., Briones, A. M., Balfagón, G., Alonso, M. J., & Salaices, M. (2005). Hypertension increases the participation of vasoconstrictor prostanoids from cyclooxygenase-2 in phenylephrine responses. Journal of Hypertension,23(4), 767–777.PubMed
61.
Virdis, A., Colucci, R., Fornai, M., Duranti, E., Giannarelli, C., Bernardini, N., et al. (2007). Cyclooxygenase-1 is involved in endothelial dysfunction of mesenteric small arteries from angiotensin II-infused mice. Hypertension,49, 679–686.PubMed
62.
Moncada, S., & Vane, J. R. (1978). Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacological Reviews,30(3), 293–331.PubMed
63.
Corriu, C., Félétou, M., Edwards, G., Weston, A. H., & Vanhoutte, P. M. (2001). Differential effects of prostacyclin and iloprost in the isolated carotid artery of the guinea-pig. European Journal of Pharmacology,426(1–2), 89–94.PubMed
64.
Parkington, H. C., Coleman, H. A., & Tare, M. (2004). Prostacyclin and endothelium-dependent hyperpolarization. Pharmacological Research,49(6), 509–514.PubMed
65.
Félétou, M., & Vanhoutte, P. (2007). Endothelium dependent hyperpolarizations: Past beliefs and presente facts. Annals of Medicine,39(7), 495–516.PubMed
66.
Gluais, P., Lonchampt, M., Morrow, J. D., Vanhoutte, P. M., & Feletou, M. (2005). Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: The Janus face of prostacyclin. British Journal of Pharmacology,146(6), 834–845.PubMedCentralPubMed
67.
Gomez, E., Schwendemann, C., Roger, S., Simonet, S., Courchay, C., Paysant, J., et al. (2008). Aging and prostacyclin responses in aorta and platelets from WKY and SHR rats. American Journal of Physiology-Heart and Circulatory Physiology,295(5), 2198–2211.
68.
Vanhoutte, P. M., & Tang, E. H. C. (2008). Endothelium-dependent contractions: When a good guy turns bad! Journal of Physiology,586(22), 5295–5304.PubMedPubMedCentral
69.
Liu, D., Li, H., Zhou, Y., Zhang, Y., Luo, W., & Liu, B. (2015). A vasoconstrictor response to COX-1-mediated prostacyclin synthesis in young rat renal arteries that increases in pre-hypertensive conditions. American Journal of Physiology-Heart and Circulatory Physiology,309, 804–811.
Metadata
Title
Chronic Mercury Exposure in Prehypertensive SHRs Accelerates Hypertension Development and Activates Vasoprotective Mechanisms by Increasing NO and H2O2 Production
Authors
P. B. A. Fardin
R. P. Simões
I. R. G. Schereider
C. C. P. Almenara
M. R. Simões
D. V. Vassallo
Publication date
01-06-2020
Publisher
Springer US
Published in
Cardiovascular Toxicology / Issue 3/2020
Print ISSN: 1530-7905
Electronic ISSN: 1559-0259
DOI
https://doi.org/10.1007/s12012-019-09545-6

Other articles of this Issue 3/2020

Cardiovascular Toxicology 3/2020 Go to the issue

OriginalPaper

The Role of Topoisomerase IIβ in the Mechanisms of Action of the Doxorubicin Cardioprotective Agent Dexrazoxane

OriginalPaper

Impact of Arterial Hypertension on Doxorubicin-Based Chemotherapy-Induced Subclinical Cardiac Damage in Breast Cancer Patients

OriginalPaper

Coenzyme Q10 Cardioprotective Effects Against Doxorubicin-Induced Cardiotoxicity in Wistar Rat

OriginalPaper

Vehicular Particulate Matter (PM) Characteristics Impact Vascular Outcomes Following Inhalation

OriginalPaper

Arbutin Attenuates Isoproterenol-Induced Cardiac Hypertrophy by Inhibiting TLR-4/NF-κB Pathway in Mice

OriginalPaper

The Effects of Neuropeptide Y Overexpression on the Mouse Model of Doxorubicin-Induced Cardiotoxicity

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits