Subchronic Arsenic Exposure Through Drinking Water Alters Lipid Profile and Electrolyte Status in Rats.

Arsenic is a groundwater pollutant and can cause various cardiovascular disorders in the exposed population. The aim of the present study was to assess whether subchronic arsenic exposure through drinking water can induce vascular dysfunction associated with alteration in plasma electrolytes and lipid profile. Rats were exposed to arsenic as 25, 50, and 100 ppm of sodium arsenite through drinking water for 90 consecutive days. On the 91st day, rats were sacrificed and blood was collected. Lipid profile and the levels of electrolytes (sodium, potassium, and chloride) were assessed in plasma. Arsenic reduced high-density lipoprotein cholesterol (HDL-C) and HDL-C/LDL-C ratio, but increased the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and electrolytes. The results suggest that the arsenic-mediated dyslipidemia and electrolyte retention could be important mechanisms in the arsenic-induced vascular disorder.

Arsenic causes aortic dysfunction and systemic hypertension in rats: Augmentation of angiotensin II signaling.

The groundwater pollutant arsenic can cause various cardiovascular disorders. Angiotensin II, a potent vasoconstrictor, plays an important role in vascular dysfunction by promoting changes in endothelial function, vascular reactivity, tissue remodeling and oxidative stress. We investigated whether modulation of angiotensin II signaling and redox homeostasis could be a mechanism contributing to arsenic-induced vascular disorder. Rats were exposed to arsenic at 25, 50 and 100ppm of sodium arsenite through drinking water consecutively for 90 days. Blood pressure was recorded weekly. On the 91st day, the rats were sacrificed for blood collection and isolation of thoracic aorta. Angiotensin converting enzyme and angiotensin II levels were assessed in plasma. Aortic reactivity to angiotensin II was assessed in organ-bath system. Western blot of AT1 receptors and G protein (Gαq/11), ELISA of signal transducers of MAP kinase pathway and reactive oxygen species (ROS) generation were assessed in aorta. Arsenic caused concentration-dependent increase in systolic, diastolic and mean arterial blood pressure from the 10th, 8th and 7th week onwards, respectively. Arsenic caused concentration-dependent enhancement of the angiotensin II-induced aortic contractile response. Arsenic also caused concentration-dependent increase in the plasma levels of angiotensin II and angiotensin converting enzyme and the expression of aortic AT1 receptor and Gαq/11 proteins. Arsenic increased aortic protein kinase C activity and the concentrations of protein tyrosine kinase, extracellular signal-regulated kinase-1/2 and vascular endothelial growth factor. Further, arsenic increased aortic mRNA expression of Nox2, Nox4 and p22phox, NADPH oxidase activity and ROS generation. The results suggest that arsenic-mediated enhancement of angiotensin II signaling could be an important mechanism in the arsenic-induced vascular disorder, where ROS could augment the angiotensin II signaling through activation of MAP kinase pathway.

Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats.

Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100ppm) through drinking water for 90 consecutive days. Atorvastatin (10mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis.

Subchronic arsenic exposure through drinking water alters vascular redox homeostasis and affects physical health in rats.

We evaluated whether arsenic can alter vascular redox homeostasis and modulate antioxidant status, taking rat thoracic aorta as a model vascular tissue. In addition, we evaluated whether the altered vascular biochemical homeostasis could be associated with alterations in the physical indicators of toxicity development. Rats were exposed to arsenic as 25, 50, and 100 ppm of sodium arsenite through drinking water for 90 consecutive days. Body weight, food intake, and water consumption were recorded weekly. On the 91st day, rats were sacrificed; vital organs and thoracic aorta were collected. Lipid peroxidation, reactive oxygen species generation, and antioxidants were assessed in the thoracic aorta. Arsenic increased aortic lipid peroxidation and hydrogen peroxide generation while decreased reduced glutathione content in a dose-dependent manner. The activities of the enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were decreased. Further, arsenic at 100 ppm decreased feed intake, water consumption, and body weight from the 11th week onward. At this concentration, arsenic increased the relative weights of the liver and kidney. The results suggest that arsenic causes dose-dependent oxidative stress, reduction in antioxidative defense systems, and body weight loss with alteration in hepato-renal organosomatic indices. Overall, subchronic arsenic exposure through drinking water causes alteration in vascular redox homeostasis and at high concentration affects physical health.

Atorvastatin restores arsenic-induced vascular dysfunction in rats: modulation of nitric oxide signaling and inflammatory mediators.

We evaluated whether atorvastatin, an extensively prescribed statin for reducing the risks of cardiovascular diseases, can reduce the risk of arsenic-induced vascular dysfunction and inflammation in rats and whether the modulation could be linked to improvement in vascular NO signaling. Rats were exposed to sodium arsenite (100ppm) through drinking water for 90 consecutive days. Atorvastatin (10mg/kg bw, orally) was administered once daily during the last 30days of arsenic exposure. On the 91(st) day, blood was collected for measuring serum C-reactive protein. Thoracic aorta was isolated for assessing reactivity to phenylephrine, sodium nitroprusside and acetylcholine; evaluating eNOS and iNOS mRNA expression and measuring NO production, while abdominal aorta was used for ELISA of cytokines, chemokine and vascular cell adhesion molecules. Histopathology was done in aortic arches. Arsenic did not alter phenylephrine-elicited contraction. Atorvastatin inhibited Emax of phenylephrine, but it augmented the contractile response in aortic rings from arsenic-exposed animals. Sodium nitroprusside-induced relaxation was not altered with any treatment. However, arsenic reduced acetylcholine-induced relaxation and affected aortic eNOS at the levels of mRNA expression, protein concentration, phosphorylation and NO production. Further, it increased aortic iNOS mRNA expression, iNOS-derived NO synthesis, production of pro-inflammatory mediators (IL-1ß, IL-6, MCP-1, VCAM, sICAM) and serum C-reactive protein and aortic vasculopathic lesions. Atorvastatin attenuated these arsenic-mediated functional, biochemical and structural alterations. Results show that atorvastatin has the potential to ameliorate arsenic-induced vascular dysfunction and inflammation by restoring endothelial function with improvement in NO signaling and attenuating production of pro-inflammatory mediators and cell adhesion molecules.