Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats Thengumpallil Sasindran Sarath a , Prashantkumar Waghe a , Priyanka Gupta a , Soumen Choudhury a , Kandasamy Kannan a , Ayyappan Harikrishna Pillai b , Sankaran Kutty Harikumar a , Santosh Kumar Mishra a , Souvendra Nath Sarkar a, ⁎ a Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India b Division of Animal Biochemistry, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India abstract article info Article history: Received 16 July 2014 Revised 28 August 2014 Accepted 31 August 2014 Available online 11 September 2014 Keywords: Arsenic Atorvastatin Blood pressure Lipid profile Redox signaling Rat 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 evaluat- ed 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 (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine produc- tion, 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 de- pleted 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. © 2014 Elsevier Inc. All rights reserved. Introduction Arsenic is a naturally occurring metalloid that is ubiquitously present in both organic and inorganic forms. People are exposed to elevated levels of inorganic arsenic through contaminated drinking water, food prepared with this water and food crops irrigated with high arsenic water sources. The greatest threat to public health originates from the arsenic contaminated groundwater. People in sever- al countries around the world, including India and Bangladesh, are exposed to arsenic via drinking of contaminated groundwater (Jiang et al., 2013). About 450 million people in the Ganga–Meghna–Brahma- putra region are prone to arsenic poisoning through contaminated groundwater (Roy et al., 2013). Though arsenic-induced cancer has been widely studied, less attention was paid to arsenic-induced vascular diseases. Epidemiological studies showed that chronic arsenic exposure was associated with increased morbidity and mortality from cardiovas- cular diseases (CVDs), including hypertension, ischemic heart disease, atherosclerosis and peripheral vascular disease (Stea et al., 2014). Oxidative stress can cause vascular endothelial dysfunction (VED) and development of CVDs (Paravicini and Touyz, 2008). Evidences indicate that arsenicals can generate reactive oxygen species (ROS), especially superoxide anion radical (O 2 • - ) and H 2 O 2 , in human vascular smooth muscle cells (VSMCs) mainly via NADPH oxidase (Nox) activa- tion and increased p22phox mRNA expression (Lynn et al., 2000). Arsenic increased O 2 • - generation in vascular endothelial cells (ECs; Toxicology and Applied Pharmacology 280 (2014) 443–454 Abbreviations: ATV, Atorvastatin; CMC, Carboxymethyl cellulose; CVD, Cardiovascular disease; cNOS, Constitutive nitric oxide synthase; DBP, Diastolic blood pressure; EC, Endothelial cell; eNOS, Endothelial nitric oxide synthase; GPx, Glutathione peroxidase; GSH, Reduced glutathione; HDL-C, High density lipoprotein cholesterol; iNOS, Inducible ni- tric oxide synthase; LDL-C, Low density lipoprotein cholesterol; LPO, Lipid peroxidation; MABP, Mean arterial blood pressure; NO, Nitric oxide; Nox, NADPH oxidase; RLU, Relative light unit; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; SA, Sodium arse- nite; SBP, Systolic blood pressure; SOD, Superoxide dismutase; VSMC, Vascular smooth mus- cle cell; VED, Vascular endothelial dysfunction. ⁎ Corresponding author. Fax: +91 581 2303284. E-mail address: snsarkar1911@rediffmail.com (S.N. Sarkar). http://dx.doi.org/10.1016/j.taap.2014.08.032 0041-008X/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Toxicology and Applied Pharmacology journal homepage: www.elsevier.com/locate/ytaap