Vascular smooth muscle dysfunction induced by monomethylarsonous acid (MMA^III): A contributing factor to arsenic-associated cardiovascular diseases

While arsenic in drinking water is known to cause various cardiovascular diseases in human, exact mechanism still remains elusive. Recently, trivalent-methylated arsenicals, the metabolites of inorganic arsenic, were shown to have higher cytotoxic potential than inorganic arsenic. To study the role of these metabolites in arsenic-induced cardiovascular diseases, we investigated the effect of monomethylarsonous acid (MMA^III), a major trivalent-methylated arsenical, on vasomotor tone of blood vessels. In isolated rat thoracic aorta and small mesenteric arteries, MMA^III irreversibly suppressed normal vasoconstriction induced by three distinct agonists of phenylephrine (PE), serotonin and endothelin-1. Inhibition of vasoconstriction was retained in aortic rings without endothelium, suggesting that MMA^III directly impaired the contractile function of vascular smooth muscle. The effect of MMA^III was mediated by inhibition of PE-induced Ca²⁺ increase as found in confocal microscopy and fluorimeter in-lined organ chamber technique. The attenuation of Ca²⁺ increase was from concomitant inhibition of release from intracellular store and extracellular Ca²⁺ influx via L-type Ca²⁺ channel, which was blocked by MMA^III as shown in voltage-clamp assay in Xenopus oocytes. MMA^III did not affect downstream process of Ca²⁺, as shown in permeabilized arterial strips. In in vivo rat model, MMA^III attenuated PE-induced blood pressure increase indeed, supporting the clinical relevance of these in vitro findings. In conclusion, MMA^III-induced smooth muscle dysfunction through disturbance of Ca²⁺ regulation, which results in impaired vasoconstriction and aberrant blood pressure change. This study will provide a new insight into the role of trivalent-methylated arsenicals in arsenic-associated cardiovascular diseases.