Arsenic-induced dysfunction in relaxation of blood vessels.

Abstract

Several epidemiological studies have suggested that exposure to arsenic is strongly correlated with the development of cardiovascular diseases such as hypertension. To determine whether arsenic affects vasomotor tone in blood vessels, we investigated the effect of arsenic on vasorelaxation using isolated rat aortic rings in an organ-bath system. Treatment with arsenite inhibited acetylcholine-induced relaxation of the aortic rings in a concentration-dependent manner, whereas several other arsenic species did not have any effect. Consistent with these findings, the levels of guanosine 3',5'-cyclic monophosphate (cGMP) in the aortic rings were significantly reduced by arsenite treatment. In cultured human aortic endothelial cells, treatment with arsenite resulted in a concentration-dependent inhibition of endothelial nitric oxide synthase (eNOS). In addition, higher concentrations of arsenite decreased the relaxation induced by sodium nitroprusside (an NO donor) and 8-Br-cGMP (a cGMP analog) in aortic rings without endothelium. These in vitro results indicate that arsenite is capable of suppressing relaxation in blood vessels by inhibiting eNOS activity in endothelial cells and by impairing the relaxation machinery in smooth muscle cells. In vivo studies revealed that the reduction of blood pressure by acetylcholine infusion was significantly suppressed after arsenite was administered intravenously to rats. These data suggest that an impairment of vasomotor tone due to arsenite exposure may be a contributing factor in the development of cardiovascular disease.

Mitochondrial Damage Mediates Genotoxicity of Arsenic in Mammalian Cells

“…Because mitochondria constitute a primary locus for the intracellular formation and reactions of peroxynitrite, which has a much longer half life compared with hydroxyl radicals and can readily diffuse across biomembranes (43), it is likely that multiple radical species are involved in the genotoxic response of arsenic. Our present findings are consistent with the observation that nitric oxide, an upstream molecule in the biosynthesis of peroxynitrite, has been implicated in endothelial cell damages associated with arsenic exposure (52).…”

Cardiovascular effects of arsenic: clinical and epidemiological findings

“…Moreover, As decreases in vitro vascular relaxation capability, both endothelium-dependent and endothelium-independent, directly acting on the smooth muscle cells (Lee et al 2003), while it potentiates response to vasoconstrictors through myosin light chain phosphorylation and Ca ++ sensitization/inflow (Lee et al 2005;Li et al 2010;Lim et al 2011). Interaction with arachidonic acid biotransformation, influencing vasoconstriction and relaxation, may be another mechanism (Bunderson et al 2004).…”

“…In addition to the direct action of ROS on NO, As inhibits endothelial NO synthetasis (eNOS) (Fig. 1) (Lee et al 2003;Tsou et al 2005;Li et al 2007), it depletes GSH -one of the main antioxidant ROS scavengers -and inhibits redox enzymes (catalase, glutathione peroxidase and reductase, thioredoxin reductase, superoxide dysmutase). The disruption of antioxidant defense mechanisms and the blocking of new NO formation further decrease NO bioavailability and increase endothelial dysfunction (Pi et al 2000).…”

Arsenic in Drinking Water and Stroke Hospitalizations in Michigan

“…5,6,30 Inhibition of endothelial nitrogen oxide synthase and enhanced vasoconstriction by arsenic provide potential mechanistic links between arsenic exposure and hypertension, a strong risk factor for ischemic stroke. 31,32 Some limitations to this work warrant discussion. Common to ecological studies, this investigation did not contain individual-level data and therefore cannot be used to infer a causal relationship between arsenic and ischemic stroke.…”