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Moo-Yeol Lee,¹ Young-Ho Lee,² Kyung-Min Lim,¹ Seung-Min Chung,¹ Ok-Nam Bae,¹ Heon Kim,³ Choong-Ryeol Lee,⁴ Jung-Duck Park,⁵ and Jin-Ho Chung¹

¹College of Pharmacy, Seoul National University, Seoul, Korea; ²College of Medicine and BK21 Project for Medical Sciences, Yonsei University, Seoul, Korea; ³College of Medicine, Chungbuk National University, Cheongju, Korea; ⁴Ulsan University Hospital, Ulsan, Korea; ⁵College of Medicine, Chung-Ang University, Seoul, Korea

Abstract
Chronic exposure to arsenic is well known as the cause of cardiovascular diseases such as hypertension. To investigate the effect of arsenic on blood vessels, we examined whether arsenic affected the contraction of aortic rings in an isolated organ bath system. Treatment with arsenite, a trivalent inorganic species, increased vasoconstriction induced by phenylephrine or serotonin in a concentration-dependent manner. Among the arsenic species tested--arsenite, pentavalent inorganic species (arsenate) , monomethylarsonic acid (MMA^V) , and dimethylarsinic acid (DMA^V) --arsenite was the most potent. Similar effects were also observed in aortic rings without endothelium, suggesting that vascular smooth muscle plays a key role in enhancing vasoconstriction induced by arsenite. This hypercontraction by arsenite was well correlated with the extent of myosin light chain (MLC) phosphorylation stimulated by phenylephrine. Direct Ca²⁺ measurement using fura-2 dye in aortic strips revealed that arsenite enhanced vasoconstriction induced by high K⁺ without concomitant increase in intracellular Ca²⁺ elevation, suggesting that, rather than direct Ca²⁺ elevation, Ca²⁺ sensitization may be a major contributor to the enhanced vasoconstriction by arsenite. Consistent with these in vitro results, 2-hr pretreatment of 1.0 mg/kg intravenous arsenite augmented phenylephrine-induced blood pressure increase in conscious rats. All these results suggest that arsenite increases agonist-induced vasoconstriction mediated by MLC phosphorylation in smooth muscles and that calcium sensitization is one of the key mechanisms for the hypercontraction induced by arsenite in blood vessels. Key words: arsenic, arsenite, blood vessels, calcium sensitization, cardiovascular disease, myosin light chain phosphorylation, vasoconstriction. Environ Health Perspect 113:1330-1335 (2005) . doi:10.1289/ehp.8000 available via http://dx.doi.org/ [Online 14 June 2005]

Address correspondence to J.-H. Chung, College of Pharmacy, Seoul National University, Shinrim-dong San 56-1, Seoul 151-742, Korea. Telephone: 82-2-880-7856. Fax: 82-2-885-4157. E-mail: jhc302@plaza.snu.ac.kr

This work was supported by the Ministry of Science and Technology National Research and Development Program and by the Eco-Technopia 21 project of the Ministry of Environment, Korea.

The authors declare they have no competing financial interests.

Received 7 February 2005 ; accepted 14 June 2005.