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ToxSci Advance Access published online on October 20, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl136
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 13, 2006
Accepted October 17, 2006

Environmental Toxicology

Involvement of Substance P and Neurogenic Inflammation in Arsenic-Induced Early Vascular Dysfunction

Shih-Chieh Chen 1, Ming-Hsien Tsai 2, Hsiu-Jen Wang 2, Hsin-Su Yu 3, and Louis W. Chang 2 *

1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University; Department of Clinical Research, Kaohsiung Medical University Hospital
2 National Health Research Institutes, Div. of Environmental Health & Occupational Medicine
3 Kaohsiung Medical University

* To whom correspondence should be addressed.
Louis W. Chang, E-mail: lwchang44{at}yahoo.com


  Abstract

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 non-specific 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 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 NK1 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.

Keywords: arsenic toxicity; vascular injury; substance P; neurogenic inflammation; vascular injury.
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