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

Ok Nam Bae, Kyung Min Lim, Jee Yeon Han, Byoung In Jung, Jin Young Lee, Ji Yoon Noh, Seung Min Chung, Moo Yeol Lee, Joo Young Lee, Jin Ho Chung

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)181-190
Number of pages10
JournalToxicological Sciences
Volume103
Issue number1
DOIs
StatePublished - May 2008

Keywords

  • Arsenic
  • Endothelial cells
  • Heterogenic responses
  • Menadione
  • Risk assessment
  • Smooth muscle cells
  • U-shaped dose response
  • Vasoconstriction

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