Potentiation of vasoconstriction and pressor response by low concentration of monomethylarsonous acid (MMAIII)

A close link between arsenic exposure and hypertension has been well-established through many epidemiological reports, yet the mechanism underlying it remains unclear. Here we report that nanomolar concentrations of monomethylarsonous acid (MMA^III), a toxic trivalent methylated arsenic metabolite, can potentiate agonist-induced vasoconstriction and pressor responses. In freshly isolated rat aortic ring, exposure to nanomolar MMA^III (100-500nM) potentiated phenylephrine (PE)-induced vasoconstriction while at higher concentrations (≥2.5μM), suppression of vasoconstriction and apoptosis of vascular smooth muscle were observed. Potentiation of agonist-induced vasoconstriction was also observed with other contractile agonists and it was retained in endothelium-denuded aortic rings, suggesting that these events are agonist-independent and smooth muscle cell dependent. Interestingly, exposure to MMA^III resulted in increased myosin light chain phosphorylation while PE-induced Ca²⁺ influx was not affected, reflecting that Ca²⁺ sensitization is involved. In line with this, MMA^III enhanced agonist-induced activation of small GTPase RhoA, a key contributor to Ca²⁺ sensitization. Of note, treatment of MMA^III to rats induced significantly higher pressor responses in vivo, demonstrating that this event can occur in vivo indeed. We believe that RhoA-mediated Ca²⁺ sensitization and the resultant potentiation of vasoconstriction by MMA^III may shed light on arsenic-associated hypertension.