Inorganic arsenite potentiates vasoconstriction through calcium sensitization in vascular smooth muscle

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.