ToxSci Advance Access originally published online on October 20, 2006
Toxicological Sciences 2007 95(1):82-88; doi:10.1093/toxsci/kfl136
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Involvement of Substance P and Neurogenic Inflammation in Arsenic-Induced Early Vascular Dysfunction
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* Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University and Department of Clinical Research, Kaohsiung Medical University Hospital, Taiwan, R.O.C.
Division of Environmental Health & Occupational Medicine, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, R.O.C.
Kaohsiung Medical University, Taiwan, R.O.C
1 To whom correspondence should be addressed at Dr Louis W. Chang, Division of Environmental Health & Occupational Medicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County, Taiwan, R.O.C. Fax: +886 37-587406. E-mail: lwchang44{at}yahoo.com.
Received September 13, 2006; accepted October 17, 2006
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Abstract |
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Vascular-related diseases, including Blackfoot Disease and atherosclerosis, are prominent clinical findings among populations residing in arseniasis areas. While oxidative stress provided a general but nonspecific mechanistic base for arsenic-induced endothelial cell damage in vitro, more specific mechanism is needed to explain the highly targeted vascular lesions induced by arsenic in vivo. Based on our previous studies, we hypothesized that arsenic exerted its action on blood vessels via the neurogenic inflammation process involving release of a neuropeptide (substance P) and activation of endothelial Neurokinin 1 (NK-1) receptor in vivo. Indeed, our present study demonstrated a significantly higher substance P levels in arsenic-treated tissues when compared to saline-treated controls indicating a rapid release of substance P under the influence of arsenic. Furthermore, the arsenic-induced vascular leakage could be significantly reduced when the neurogenic inflammation process was interrupted (via either disruption on the release of substance P, interference on the action of substance P, or blockage of endothelial NK-1 receptor) showing that the neurogenic inflammation process was indeed involved. Histamine release was not found to play a significant role in arsenic-induced vascular permeability change. Our present study affirmed a de novo concept that a pathophysiological mechanism involving the neurogenic release of substance P and activation of endothelial NK-1 receptor underlies the arsenic-induced vascular injury and dysfunction in vivo. This pathophysiological process constituted a two-tiered biological interaction between the nervous system and vascular system and therefore was not readily unveiled by traditional in vitro studies in the past. Our present finding unveiled an important de novo concept on arsenic vascular toxicity in vivo.
Key Words: arsenic toxicity; vascular injury; substance P; neurogenic inflammation; vascular injury.
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