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Toxicology. 2017 Sep 1;390:10-21. doi: 10.1016/j.tox.2017.08.004. Epub 2017 Aug 19.

Aluminum exposure at human dietary levels promotes vascular dysfunction and increases blood pressure in rats: A concerted action of NAD(P)H oxidase and COX-2.

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Postgraduate Program in Biochemistry, Universidade Federal do Pampa, BR 472 - Km 592 - PO box 118, Zip Code: 97500-970, Uruguaiana, Rio Grande do Sul, Brazil.
Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Avda. de Atenas s/n, Alcorcón, Spain; Ciber de Enfermedades Cardiovasculares, Spain.
Departments of Physiological Sciences, Universidade Federal do Espírito Santo and School of Medicine of Santa Casa de Misericórdia (EMESCAM), Av. Marechal Campos 1468, Zip Code: 29040-090, Vitória, Espírito Santo, Brazil.
The Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire ST5 5BG, UK.
Bioactivity and Food Analysis Laboratory, Instituto de Investigación en Ciencias de la Alimentación, Nicolás Cabrera, 9, Campus Universitario de Cantoblanco, Madrid, Spain.
Ciber de Enfermedades Cardiovasculares, Spain; Department of Pharmacology, Universidad Autónoma de Madrid, Instituto de Investigación Hospital La Paz (IdiPaz), C/ Arzobispo Morcillo 4, 28029, Madrid, Spain.
Postgraduate Program in Biochemistry, Universidade Federal do Pampa, BR 472 - Km 592 - PO box 118, Zip Code: 97500-970, Uruguaiana, Rio Grande do Sul, Brazil. Electronic address:


Aluminum (Al) is a non-essential metal and a significant environmental contaminant and is associated with a number of human diseases including cardiovascular disease. We investigated the effects of Al exposure at doses similar to human dietary levels on the cardiovascular system over a 60day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60days as follows: a) Untreated - ultrapure water; b) AlCl3 at a dose of 8.3mg/kg bw for 60days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42days as follows: C) Untreated - ultrapure water; d) AlCl3 at 100mg/kg bw for 42days, representing a high level of human exposure to Al. Effects on systolic blood pressure (SBP) and vascular function of aortic and mesenteric resistance arteries (MRA) were studied. Endothelium and smooth muscle integrity were evaluated by concentration-response curves to acetylcholine (ACh) and sodium nitroprusside. Vasoconstrictor responses to phenylephrine (Phe) in the presence and absence of endothelium and in the presence of the NOS inhibitor L-NAME, the potassium channels blocker TEA, the NAD(P)H oxidase inhibitor apocynin, superoxide dismutase (SOD), the non-selective COX inhibitor indomethacin and the selective COX-2 inhibitor NS 398 were analyzed. Vascular reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity, were measured. The mRNA expressions of eNOS, NAD(P)H oxidase 1 and 2, SOD1, COX-2 and thromboxane A2 receptor (TXA-2 R) were also investigated. Al exposure at human dietary levels impaired the cardiovascular system and these effects were almost the same as Al exposure at much higher levels. Al increased SBP, decreased ACh-induced relaxation, increased response to Phe, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide (NO), the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric arteries. Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Our results point to an excess of ROS mainly from NAD(P)H oxidase after Al exposure and the increased vascular prostanoids from COX-2 acting in concert to decrease NO bioavailability, thus inducing vascular dysfunction and increasing blood pressure. Therefore, 60-day chronic exposure to Al, which reflects common human dietary Al intake, appears to pose a risk for the cardiovascular system.


Cardiovascular risk; Metal; Oxidative stress; Vascular impairment

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