ToxSci Advance Access originally published online on February 14, 2008
Toxicological Sciences 2008 103(1):181-190; doi:10.1093/toxsci/kfn023
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U-shaped Dose Response in Vasomotor Tone: A Mixed Result of Heterogenic Response of Multiple Cells to Xenobiotics
* College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
AMOREPACIFIC CO/R&D Center, Gyeonggi-do 446-729, South Korea
College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea
1 To whom correspondence should be addressed at Jin-Ho Chung, College of Pharmacy, Seoul National University, Shinrim-dong San 56-1, Seoul 151-742, South Korea. Fax: +82-2-885-4157. E-mail: jhc302{at}snu.ac.kr.
Received August 21, 2007; accepted January 23, 2008
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Abstract |
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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 K3), 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.
Key Words: U-shaped dose response; vasoconstriction; arsenic; menadione; endothelial cells; smooth muscle cells; heterogenic responses; risk assessment.