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U-shaped dose response in vasomotor tone: A mixed result of heterogenic response of multiple cells to xenobiotics

Title
U-shaped dose response in vasomotor tone: A mixed result of heterogenic response of multiple cells to xenobiotics
Author
배옥남
Keywords
U-shaped dose response; vasoconstriction; arsenic; menadione; endothelial cells; smooth muscle cells; heterogenic responses; risk assessment
Issue Date
2008-04
Publisher
OXFORD UNIV PRESS
Citation
TOXICOLOGICAL SCIENCES, v. 103, No. 1, Page. 181-190
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.
URI
https://academic.oup.com/toxsci/article/103/1/181/1695187http://repository.hanyang.ac.kr/handle/20.500.11754/80292
ISSN
1096-6080
DOI
10.1093/toxsci/kfn023
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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