A Exposição Crônica e Baixas Doses de Cloreto de Mercúrio Altera a Reatividade Vascular da Artéria Aorta de Ratos. Papel das Espécies Reativas do Oxigênio e dos Prostanóides da Via da Ciclooxigenase .
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2009-05-07
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Pecanha, Franck Maciel
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Universidade Federal do Espírito Santo
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Mercury exposure produces toxic effects in central nervous system and kidneys. Recently these toxic effects were associated to cardiovascular events but the underlying mechanisms are not well explored. The main purpose of this study was to investigate if mercury exposure at low doses alters vasoconstrictor prostanoids production from cyclooxygenase-2 (COX-2) and its contribution to phenylephrine vasoconstrictor responses and acetylcholine vasodilator responses. For this were developed an experimental model of exposure to low doses of mercury chloride (HgCl2) and evaluated the effect of this exposure on systolic blood pressure (SBP), the participation of products derived from the endothelium, prostanoids derived from the cyclooxygenase-2 (COX-2), reactive oxygen species (ROS) and the reninangiotensin system in vascular reactivity in conductance arteries. Aortic segments from 3-month old Wistar rats daily treated with HgCl2 (1st dose 4.6 µg/kg, subsequent dose 0.07 µg/kg/day, i.m) or vehicle for 30 days were used. The vascular reactivity experiments were performed in an organ bath, the atomic absorption spectrometry for determination of blood concentration of mercury, RT-PCR and Western blot to verify the gene and protein expression, confocal microscopy analyzed levels of superoxide anion and structure of arteries. A commercial kit used to determine the production of prostanoids derived from COX-2 pathway. The activity of angiotensinconverting enzyme (ACE) was measured by fluorometry method and SBP by tail plethysmography. Blood levels of mercury at the end of treatment were 7.97 ± 0.59 ng/ml. Mercury treatment did not affect systolic blood pressure, but increased phenylephrine contractile responses, reduced acetylcholine-induced vasodilatation and did not change the vasodilatation by the nitric oxide donor, DEA-NO, in aortic rings. The contractile prostanoids derived from COX-2 pathway, reactive oxygen species (ROS) and increased plasmatic ACE activity were related to these responses. Increased production of EROS, increased plasma ACE activity, increased gene expression of mRNA for COX-2 and increased production of contractile prostanoids (PGE2 and TXA2) derived from COX-2 were observed in animals exposed to mercury and reinforce the hypothesis of a greater involvement of these pathways in the alteration of vascular response to phenylephrine. In the presence of superoxide dismutase (SOD) the vasodilator response to acetylcholine was improved in rats of the mercury group, indicating that endothelial dysfunction appears to be responsible for the increased production of EROS. The extracellular SOD (EC-SOD) expression was increased by exposure to mercury. These results suggest that this new experimental model of chronic exposure at low concentrations of HgCl2 promotes endothelial dysfunction due to the reduced bioavailability of NO induced by increased oxidative stress, and increase the contractile response to phenylephrine with greater involvement of the reninangiotensin system, EROS and contractile prostanoids derived from COX-2 pathway in this response. These results help to clarify the mechanisms by which mercury at low doses exerts toxic effects on the cardiovascular system and can be considered a risk factor for development of cardiovascular disease.
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PEÇANHA, Franck Maciel. A Exposição Crônica e Baixas Doses de Cloreto de Mercúrio Altera a Reatividade Vascular da Artéria Aorta de Ratos. Papel das Espécies Reativas do Oxigênio e dos Prostanóides da Via da Ciclooxigenase . 2009.Tese (Doutorado em Ciências Fisiológicas) - Universidade Federal do Espírito Santo, Centro de Ciências da Saúde, Vitória, 2009.