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 (MMAIII), a toxic trivalent methylated arsenic metabolite, can potentiate agonist-induced vasoconstriction and pressor responses. In freshly isolated rat aortic ring, exposure to nanomolar MMAIII (100–500 nM) potentiated phenylephrine (PE)-induced vasoconstriction while at higher concentrations (≥2.5 μM), 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 MMAIII 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, MMAIII enhanced agonist-induced activation of small GTPase RhoA, a key contributor to Ca2+ sensitization. Of note, treatment of MMAIII 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 MMAIII may shed light on arsenic-associated hypertension.

► A close link between arsenic and hypertension is well-established.
► We examined effects of monomethylarsonous acid (MMAIII) on vasoconstriction.
► MMAIII potentiated agonist-induced vasoconstriction and pressor response in rats.
► RhoA activation and resultant Ca2+ sensitization mediated these events.
► Ca2+ sensitization by MMAIII may explain arsenic-associated hypertension.