title: Potentiation of vasoconstriction and pressor response by low concentration of monomethylarsonous acid (MMA(III)).
abstract: 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) (100-500 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 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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
authors.forename: Yoo-Sun
authors.initials: YS
authors.lastname: Shin
authors.forename: Seojin
authors.initials: S
authors.lastname: Kang
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Noh
authors.forename: Keunyoung
authors.initials: K
authors.lastname: Kim
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Chung
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects; D020261:Arsenic Poisoning / Q000503:physiopathology; D001152:Arsenicals / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000209:etiology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D009942:Organometallic Compounds / Q000633:toxicity*; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D011311:Pressoreceptors / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D020742:rhoA GTP-Binding Protein / Q000819:agonists
chemical_list: D001152:Arsenicals; D018994:Myosin Light Chains; D009942:Organometallic Compounds; D014662:Vasoconstrictor Agents; C406082:monomethylarsonous acid; D020742:rhoA GTP-Binding Protein