Cadmium is a highly toxic metal that is present in phosphate fertilizers, and the incidence of cadmium poisoning in the general population has increased, mainly due to cigarette smoking. Once absorbed, cadmium accumulates in the tissues, causing harmful effects including high blood pressure, endothelial damage and oxidative stress. Oxidative stress is known to efficiently produce oxidized low-density lipoprotein and consequently atherosclerosis, mainly in the aorta. However, the mechanisms through which endothelial damage is induced by cadmium have not been elucidated. Thus, the aim of this study was to investigate the effects of this metal in the isolated aorta and the possible role of oxidative stress. Rats received 100 mg.L？1 cadmium chloride (CdCl2) in the drinking water or distilled water alone for four weeks. The pressor effect of cadmium was followed throughout the exposure period by tail plethysmography. At the end of the fourth week, the blood cadmium content was established, and the vascular reactivity of the isolated aorta to phenylephrine, acetylcholine and sodium nitroprusside was analyzed in the context of endothelium denudation and incubation with L-NAME, apocynin, losartan, enalapril, superoxide dismutase (SOD) or catalase. We observed an increased response to phenylephrine in cadmium-treated rats. This increase was abolished by catalase and SOD incubation. Apocynin treatment reduced the phenylephrine response in both treatment groups, but its effect was greater in cadmium-treated rats, and NOX2 expression was greater in the cadmium group. These results suggested that cadmium in blood concentrations similar to those found in occupationally exposed populations is able to stimulate NOX2 expression, contributing to oxidative stress and reducing NO bioavailability, despite enhanced eNOS expression. These findings suggest that cadmium exposure promotes endothelial damage that might contribute to inflammation, vascular injury and the development of atherosclerosis.
World Health Organization. (1992) Cadmium. Environmental Health Criteria 134. WHO International Programme on Chemical Safety (IPCS), Geneva, Switzerland.
Agency for Toxic Substances and Disease Registry (ATSDR). (2008) Toxicological Profile for Cadmium (Draft for Public Comment). Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
Afridi HI, Kazi TG, Kazi NG, Jamali MK, Arain MB, et al. (2010) Evaluation of cadmium, lead, nickel and zinc status in biological samples of smokers and non smokers hypertensive patients. J Human Hypertension 24: 34–43.
Sato M, Kondoh M (2002) Recent studies on metallotionein protection against toxicity of heavy metals and oxygen free radicals. Tohoky J Exp Med 196: 9–12.
Satarug S, Nishijo M, Ujjin P, Vanavanitkun Y, Moore MR (2005) Cadmium-induced nephopathy in the development of high blood pressure. Toxicol Lett 157: 57–68.
Zhang W, Fievez L, Cheu E, Bureau F, Rong W, et al. (2010) Anti-inflammatory effects of formoterol and ipratropium bromide against acute cadmium-induced pulmonary inflammation in rats. Eur J Pharmacol. 628(1–3): 171–178.
Nishijo M, Morikawa Y, Nakagawa H, Tawara K, Miura K, et al. (2006) Causes of death and renal tubular dysfunction in residents exposed to cadmium in the environment. Occup Environ Med 63 (8): 545–550.
Nawrot TS, Van Hecke E, Thiys L, Richart T, Kuznetsova T, et al. (2008) Cadmium related mortality and long term secular trend in the cadmium body burden of an environmental exposed population. Environ Health Perspect 116: 1620–1628.
Menke A, Muntner P, Silbergeld EK, Platz EA, Guallar E (2009) Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect 117(2): 190–6.
Donpunha W, Konungviriyapan U, Sompamit K, Pakdeechote P, Konungviriyapan V, et al. (2011) Protective effect of ascorbic acid on cadmium-induced hypertension and vascular dysfunction in mice. Biometals 24: 105–115.
Prozialeck WC, Edwards JR, Nerbert DW, Woods JM, Barchowsky A, et al. (2007) The vascular system as a target of metal toxicity. Toxicol Sci 102: 207–218.
Yoopan N, Watcharasit P, Wongsawatkul O, Piyachaturawat P, Satayavivad J (2008) Atenuation of eNOS expression in cadmium-induced hypertensive rats. Toxicol Lett 176: 157–161.
Takahashi Y, Poteser M, Masui H, Koizumi N, Wakabayashi I (2004) Effects of cadmium in vitro on contractile and relaxant responses of isolated rat aortas. Environ Health Prev Med. 9(6): 251–6.
Carageorgiou H, Tzotzes V Sideris A, Zarros A Tsakiris S (2005) Cadmium effects on brain acetylcholinesterase activity and antioxidante status of adult rats: modulation by zinc, calcium and L-cysteine co-administration. Basic Clin Pharmacol Toxicol 97: 320–324.
Gokalp O, Ozdem S, Donmez S, Dogan M, Demerin H, et al. (2009) Impairment of endothelium-dependent vasorelaxation in cadmium-hypertensive rats. Toxicol Ind Health 25: 447–453.
Mitra S, Deshmukh A, Sachdeva R, Lu J, Mehta JL (2011) Oxidized low-density lipoprotein and atherosclerosis implications in antioxidant therapy. Am J Med Sci. 342: 135–142.
Harja E, Bu DX, Hudson BI, Chang JS, Shen X, et al. (2008) Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE？/？ mice. J Clin Invest 118: 183–194.
Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, et al. (2004) Lead, Cadmium, Smoking, and Increased Risk of Peripheral Arterial Disease. Circulation 109: 3196–3201.
Vassallo DV, Sim？es MR, Furieri LB, Fioresi M, Fiorim J, et al. (2011) Toxic effects of mercury, lead and gadolinium on vascular reactivity. Braz J Med Biol Res 44(9): 939–946.
Grizzo LT, Cordellini S (2008) Perinatal Lead exposure affects nitric oxide and cyclooxygenase pathways in aorta of weaned rats. Toxicol Sci 103(1): 207–214.
Martín MC, Balfagón G, Minoves N, Blanco-Rivero J, Ferrer M (2005) Androgen deprivation increases neuronal nitric oxide metabolism and its vasodilator effect in rat mesenteric arteries. Nitric Oxide 12: 163–176.
Tzotzes V, Tzilalis V, Giannakakis S, Saranteas T, Papas A, et al. (2007) Effects of acute and chronic cadmium administration on the vascular reactivity of rat aorta. Biometals. 20(1): 83–91.
Pinheiro MC, Macchi BM, Vieira JL, Oikawa T, Amoras WW, et al. (2008) Mercury exposure and antioxidant defenses in women: a comparative study in the Amazon. Environ Res 107: 53–59.
Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG (2000) Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hidrogen peroxide. Cir Res 86: 347–354.
Gaubin Y, Vaissade F, Croute F, Beau B, Soleilhavoup J, et al. (2000) Implication of free radicals and glutathione in the mechanism of cadmium-induced expression of stress proteins in the A549 human lung cell-line. Biochim Biophys Acta 1495: 4–13.
Tandon SK, Singh S, Prasad S, Khandekar K, Dwivedi VK, et al. (2003) Reversal of cadmium induced oxidative stress by chelanting agent, antioxidant or their combination in rat. Toxicol Lett 10 145(3): 211–7.
Messner B, Bernhard D (2010) Cadmium and cardiovascular diseases: cell biology, pathophysiology, and epidemiological relevance. Biometals. 23(5): 811–22.
White SJ, Hayes EM, Lehouse S, Jeremy JY, Horvvoets AJ, et al. (2011) Characterization of the differential response of endothelial cells exposed to normal and elevated laminar sheer stress. J Cell Physiol 226(11): 2841–2848.
Manca D, Ricard AC, Trottier B, Chevalier G (1991) Studies on lipid peroxidation in rat tissues following administration of low and moderate doses of cadmium chloride. Toxicology 67: 303–23.
Bertín G, Averbeck D (2006) Cadmium: cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review). Biochimie 88: 1549–1559.
Ozturk IM, Buyukakilli B, Balli E, Cimen B, Gunes S, et al. (2009) Determination of acute and chronic effects of cadmium on the cardiovascular system of rats. Toxicol Mech And Methods 19(4): 308–317.
