Inorganic Arsenite Potentiates Vasoconstriction through Calcium Sensitization in Vascular Smooth Muscle
Lee, Moo-Yeol, Lee, Young-Ho, Lim, Kyung-Min, Chung, Seung-Min, Bae, Ok-Nam, Kim, Heon, Lee, Choong-Ryeol, Park, Jung-Duck, Chung, Jin-Ho, Environmental Health Perspectives
Chronic exposure to arsenic is well known as the cause of cardiovascular diseases such as hypertension. To investigate the effect of arsenic on blood vessels, we examined whether arsenic affected the contraction of aortic rings in an isolated organ bath system. Treatment with arsenite, a trivalent inorganic species, increased vasoconstriction induced by phenylephrine or serotonin in a concentration-dependent manner. Among the arsenic species tested--arsenite, pentavalent inorganic species (arsenate), monomethylarsonic acid (MM[A.sup.V]), and dimethylarsinic acid (DM[A.sup.V])--arsenite was the most potent. Similar effects were also observed in aortic rings without endothelium, suggesting that vascular smooth muscle plays a key role in enhancing vasoconstriction induced by arsenite. This hypercontraction by arsenite was well correlated with the extent of myosin light chain (MLC) phosphorylation stimulated by phenylephrine. Direct [Ca.sup.2+] measurement using fura-2 dye in aortic strips revealed that arsenite enhanced vasoconstriction induced by high [K.sup.+] without concomitant increase in intracellular [Ca.sup.2+] elevation, suggesting that, rather than direct [Ca.sup.2+] elevation, [Ca.sup.2+] sensitization may be a major contributor to the enhanced vasoconstriction by arsenite. Consistent with these in vitro results, 2-hr pretreatment of 1.0 mg/kg intravenous arsenite augmented phenylephrine-induced blood pressure increase in conscious rats. All these results suggest that arsenite increases agonist-induced vasoconstriction mediated by MLC phosphorylation in smooth muscles and that calcium sensitization is one of the key mechanisms for the hypercontraction induced by arsenite in blood vessels. Key words: arsenic, arsenite, blood vessels, calcium sensitization, cardiovascular disease, myosin light chain phosphorylation, vasoconstriction. Environ Health Perspect 113:1330-1335 (2005). doi: 10.1289/ehp.8000 available via http://dx.doi.org/[Online 14 June 2005]
Arsenic is a ubiquitous element distributed in the environment, and millions of people are chronically exposed to arsenic worldwide (Abernathy et al. 1999). Naturally contaminated drinking water is the main source of arsenic exposure, posing potential risk to human health (Nordstrom 2002; Schoen et al. 2004; Smith et al. 2002). Chronic arsenic exposure has been associated with a wide range of illnesses including cancer, hyperkeratosis, diabetes, and cardiovascular disease (Engel et al. 1994; Rossman 2003; Tseng 2004; Yu et al. 1984). Cardiovascular effects of arsenic exposure include hypertension, atherosclerosis, cerebrovascular disease, ischemic heart disease, and peripheral vascular disorders such as black-foot disease (resulting from gangrene caused by obstruction of peripheral blood vessels) in humans (Chen et al. 1995, 1996; Chiou et al. 1997; Rahman et al. 1999; Simeonova et al. 2003; Wang et al. 2002).
Lee et al. (2002) recently suggested that the mechanism for arsenic-induced cardiovascular disease is the increased susceptibility of platelets to aggregate, resulting in enhanced arterial thrombosis. Other mechanisms may also be responsible for the diversity of human cardiovascular disease from chronic arsenic exposure. One possibility is that arsenic may alter the normal vasomotor tone of blood vessels, which rises from contractility of vascular smooth muscle cells.
The contraction of smooth muscle is regulated by mediators such as neural and humoral factors, mechanical forces, and vasoactive substances from endothelial cells. Vascular smooth muscle contraction is triggered primarily by a rise in intracellular free [Ca.sup.2+] concentration (Sanders 2001). [Ca.sup.2+] binds to calmodulin (CAM), allowing [Ca.sup.2+]--CaM complex formation, which binds to and activates myosin light chain kinase (MLCK) (Horowitz et al. 1996). The active MLCK catalyzes the phosphorylation of the regulatory myosin light chain (MLC), which then triggers myosin--actin interaction, leading to the shortening of muscle and generation of force. …