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.
Bae
Ok-Nam
ON
College of Pharmacy, Seoul National University, Shinrim-dong San 56-1, Seoul, Republic of Korea.
Lim
Eun-Kyung
EK
Lim
Kyung-Min
KM
Noh
Ji-Yoon
JY
Chung
Seung-Min
SM
Lee
Moo-Yeol
MY
Yun
Yeo-Pyo
YP
Kwon
Seong-Chun
SC
Lee
Jun-Ho
JH
Nah
Seung-Yeol
SY
Chung
Jin-Ho
JH
D000818:Animals; D001151:Arsenic / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000209:etiology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009942:Organometallic Compounds / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D020746:Calcium Channels, L-Type; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C406082:monomethylarsonous acid; D007770:L-Lactate Dehydrogenase; D001151:Arsenic; D002118:Calcium