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

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

Toxicology and applied pharmacology (2014-07-25)
Manickam Kesavan, Thengumpallil Sasindran Sarath, Kandasamy Kannan, Subramaniyam Suresh, Priyanka Gupta, Karunakaran Vijayakaran, Palanisamy Sankar, Nitin Pandurang Kurade, Santosh Kumar Mishra, Souvendra Nath Sarkar
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Arsenic, powder, ≥99.997% trace metals basis
Sigma-Aldrich
Arsenic, 99.999% trace metals basis
Sigma-Aldrich
Fluorescein, for fluorescence, free acid
Supelco
Diazepam solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Fluorescein, European Pharmacopoeia (EP) Reference Standard
Supelco
Sodium Nitroprusside, Pharmaceutical Secondary Standard; Certified Reference Material