title: Atorvastatin restores arsenic-induced vascular dysfunction in rats: modulation of nitric oxide signaling and inflammatory mediators.
abstract: 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-1β, 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.
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Manickam
authors: M
authors: Kesavan
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Thengumpallil Sasindran
authors: TS
authors: Sarath
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Kandasamy
authors: K
authors: Kannan
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Subramaniyam
authors: S
authors: Suresh
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Priyanka
authors: P
authors: Gupta
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Karunakaran
authors: K
authors: Vijayakaran
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Palanisamy
authors: P
authors: Sankar
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Nitin Pandurang
authors: NP
authors: Kurade
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India.
authors: Santosh Kumar
authors: SK
authors: Mishra
authors: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh, India. Electronic address: snsarkar1911@rediffmail.com.
authors: Souvendra Nath
authors: SN
authors: Sarkar
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001151:Arsenic / Q000633:toxicity*; D000069059:Atorvastatin; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D009924:Organ Culture Techniques; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D011758:Pyrroles; D009569:Nitric Oxide; D000069059:Atorvastatin; D001151:Arsenic
keywords: Arsenic; Atorvastatin; Inflammatory mediators; Nitric oxide signaling; Rat; Vascular dysfunction