Toxic effects of mercury, lead and gadolinium on vascular reactivity

Heavy metals have been used in a wide variety of human activities that have significantly increased both professional and environmental exposure. Unfortunately, disasters have highlighted the toxic effects of metals on different organs and systems. Over the last 50 years, the adverse effects of chronic lead, mercury and gadolinium exposure have been underscored. Mercury and lead induce hypertension in humans and animals, affecting endothelial function in addition to their other effects. Increased cardiovascular risk after exposure to metals has been reported, but the underlying mechanisms, mainly for short periods of time and at low concentrations, have not been well explored. The presence of other metals such as gadolinium has raised concerns about contrast-induced nephropathy and, interestingly, despite this negative action, gadolinium has not been defined as a toxic agent. The main actions of these metals, demonstrated in animal and human studies, are an increase of free radical production and oxidative stress and stimulation of angiotensin I-converting enzyme activity, among others. Increased vascular reactivity, highlighted in the present review, resulting from these actions might be an important mechanism underlying increased cardiovascular risk. Finally, the results described in this review suggest that mercury, lead and gadolinium, even at low doses or concentrations, affect vascular reactivity. Acting via the endothelium, by continuous exposure followed by their absorption, they can increase the production of free radicals and of angiotensin II, representing a hazard for cardiovascular function. In addition, the actual reference values, considered to pose no risk, need to be reducedResearch supported by CAPES and CNPq/FAPES/ FUNCITEC (#39767531/07), Brazil, and MCINN (#SAF 2009-07201) and ISCIII (Red RECAVA, #RD06/0014/0011), Spai

Low mercury concentration produces vasoconstriction, decreases nitric oxide bioavailability and increases oxidative stress in rat conductance artery.

Mercury is an environmental pollutant that reduces nitric oxide (NO) bioavailability and increases oxidative stress, having a close link with cardiovascular diseases, as carotid atherosclerosis, myocardial infarction, coronary heart disease and hypertension. One of the main sites affected by oxidative stress, which develops atherosclerosis, is the aorta. Under acute exposure to low mercury concentrations reactive oxygen species (ROS) production were only reported for resistance vessels but if low concentrations of mercury also affect conductance arteries it is still unclear. We investigated the acute effects of 6 nM HgCl(2) on endothelial function of aortic rings measuring the reactivity to phenylephrine in rings incubated, or not, with HgCl(2) for 45 min, the protein expression for cyclooxygenase 2 (COX-2) and the AT1 receptor. HgCl(2) increased Rmax and pD2 to phenylephrine without changing the vasorelaxation induced by acetylcholine and sodium nitroprusside. Endothelial damage abolished the increased reactivity to phenylephrine. The increase of Rmax and pD2 produced by L-NAME was smaller in the presence of HgCl(2). Enalapril, losartan, indomethacin, furegrelate, the selective COX-2 inhibitor NS 398, superoxide dismutase and the NADPH oxidase inhibitor apocynin reverted HgCl(2) effects on the reactivity to phenylephrine, COX-2 protein expression was increased, and AT1 expression reduced. At low concentration, below the reference values, HgCl(2) increased vasoconstrictor activity by reducing NO bioavailability due to increased ROS production by NADPH oxidase activity. Results suggest that this is due to local release of angiotensin II and prostanoid vasoconstrictors. Results also suggest that acute low concentration mercury exposure, occurring time to time could induce vascular injury due to endothelial oxidative stress and contributing to increase peripheral resistance, being a high risk factor for public health

Response to β-adrenergic stimuli.

<p>The effect of myocardial infarction in rats with continuous exposure to HgCl₂ on isoproterenol (ISO, 10⁻⁴ M) conditions compared to steady-state condition of isometric force. The results are reported as the means ± SEM for 10–12 animals per group. MI = myocardial infarction; # P<0.05 <i>vs</i> Control (one-way repeated measures ANOVA followed by the Tukey's <i>post hoc</i> test).</p

Basal measurements from the right ventricle strips.

<p>The effect of myocardial infarction in rats with continuous exposure to HgCl₂ on the basal conditions of isometric force (A), time to peak tension (B), relaxation time to 90% (C), +dF/dt (D) and −dF/dt (E) of rat right ventricular strips from the Control, MI and HgCl₂-MI groups. The results are reported as the means ± SEM for 10–12 animals per group. MI = myocardial infarction; dF/dt = time derivatives of right ventricular force development. *P<0.05 <i>vs</i> Control and HgCl₂-MI; # P<0.05 <i>vs</i> Control (one-way ANOVA followed by Tukey's <i>post hoc</i> tests).</p

Functional assessment of sarcoplasmic reticulum.

<p>The effect of myocardial infarction in rats with continuous exposure to HgCl₂ on relative potentiation (ratio of post-rest contractions and steady-state contractions) of isometric contractions obtained after a 15, 30, and 60 s pause in rat right ventricular strips from the Control, MI and HgCl₂-MI groups. The results are reported as the means ± SEM for 10–12 animals per group. MI = myocardial infarction. # P<0.05 <i>vs</i> Control in the same time pause (one-way ANOVA followed by Tukey's <i>post hoc</i> tests).</p

The effect of apocynin (0.3 mM) on the concentration-response curves for phenylephrine in aortic rings in control (CT) conditions or HgCl2 (A,B).

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. Number of animals used in parentheses. (C) Differences in the area under the concentration-response curve (dAUC) in aortic rings cultured the presence and absence apocynin (0.3 mM), under control (CT) conditions or HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test.</p

Measurements of sarcolemmal calcium influx.

<p>The effect of myocardial infarction in rats with continuous exposure to HgCl₂ on relative potentiation (ratio of post-rest contraction and steady-state contractions) of isometric contractions obtained after a 15 min pause in rat right ventricular strips from the Control, MI and HgCl₂-MI groups. The results are reported as the means ± SEM for 10–12 animals per group. MI = myocardial infarction.*P<0.05 <i>vs</i> Control and HgCl₂-MI; & P<0.05 <i>vs</i> Control and MI (one-way ANOVA followed by Tukey's <i>post hoc</i> tests).</p

(A, B) The effect of indomethacin (Indo, 10 µM), on the concentration-response curves for phenylephrine in aortic rings in control (CT) conditions or HgCl2.

<p>Results (mean±SEM) are expressed as a percentage of the response to 75 mmol/l KCl. *<i>P</i><0.05 by ANOVA. Number of animals used in parentheses. (C) Differences in the area under the concentration-response curve (dAUC) in aortic rings cultured in the presence of indomethacin (10 µM) under control (CT) conditions and after acute incubation with mercury HgCl₂. *<i>P</i><0.05 by Student’s <i>t</i>-test.</p

Right ventricle proteins levels.

<p>The effect of myocardial infarction in rats with continuous exposure to HgCl₂ on the densitometry analysis of the Western blot for SERCA2a (A), PLB (B), PLB phosphorylated at serine 16 (C), SERCA/PLB ratio (D), NCX (E) in rat right ventricular strips from Control, MI and HgCl₂-MI groups. The results are reported as the means ± SEM for 5–6 animals per group. MI = myocardial infarction; * P<0.05 <i>vs</i> Control and HgCl₂-MI; # P<0.05 <i>vs</i> Control; & P<0.05 <i>vs</i> Control and MI (one-way ANOVA followed by the Tukey's <i>post hoc</i> test).</p