U-shaped dose response in vasomotor tone: A mixed result of heterogenic response of multiple cells to xenobiotics
- Authors
- Bae, Ok-Nam; Lim, Kyung-Min; Han, Jee-Yeon; Jung, Byoung-In; Lee, Jin-Young; Noh, Ji-Yoon; Chung, Seung-Min; Lee, Moo-Yeol; Lee, Joo-Young; Chung, Jin-Ho
- Issue Date
- May-2008
- Publisher
- Oxford University Press
- Keywords
- U-shaped dose response; vasoconstriction; arsenic; menadione; endothelial cells; smooth muscle cells; heterogenic responses; risk assessment
- Citation
- Toxicological Sciences, v.103, no.1, pp.181 - 190
- Indexed
- SCIE
SCOPUS
- Journal Title
- Toxicological Sciences
- Volume
- 103
- Number
- 1
- Start Page
- 181
- End Page
- 190
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/42521
- DOI
- 10.1093/toxsci/kfn023
- ISSN
- 1096-6080
- Abstract
- U-shaped response has been frequently encountered in various biological areas including epidemiology, toxicology, and oncology. Despite its frequent observation, the theory of U-shaped response has been crippled by the lack of a robust mechanism underlying and incomplete in vitro and in vivo correlation. In the present study, a novel mechanism is provided for a U-shaped response, based on the findings of agonist-induced vasomotor tone change affected by menadione (MEN) (synthetic vitamin K-3), a reactive oxygen species generator, and arsenic, an environmental pollutant, which showed typical U-shaped responses in both in vitro aortic contractile response and in vivo blood pressure. U-shaped responses by MEN and arsenic were a combined result from heterogenic susceptibilities and responses of multiple target cells composing blood vessels, that is, endothelium and smooth muscle. Notably, endothelium, a regulator of vasomotor tone, was primarily affected by low-dose stimuli, whereas smooth muscle, an effector of vascular contraction, was affected later by high-dose. The dysfunction of smooth muscle was produced by high-dose MEN-induced hydrogen peroxide, resulting in the attenuation of vascular contractile reactivity, whereas low-dose MEN-induced superoxide led to the quenching of vasodilatory nitric oxide in endothelial cells, resulting in the enhancement of vasoconstriction. This mechanistic theory, the difference in susceptibilities and responses to a common stimulus between regulator and effector components of a system, could give a new insight into the explanation of various U-shaped responses and provide a new evidence for the need of the risk assessment of toxicants with a wider dose range.
- Files in This Item
-
Go to Link
- Appears in
Collections - COLLEGE OF PHARMACY > DEPARTMENT OF PHARMACY > 1. Journal Articles
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.