U-shaped dose response in vasomotor tone: a mixed result of heterogenic response of multiple cells to xenobiotics.
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.
Bae
Ok-Nam
ON
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Lim
Kyung-Min
KM
Han
Jee-Yeon
JY
Jung
Byoung-In
BI
Lee
Jin-Young
JY
Noh
Ji-Yoon
JY
Chung
Seung-Min
SM
Lee
Moo-Yeol
MY
Lee
Joo-Young
JY
Chung
Jin-Ho
JH
D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D049449:Luminescence; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D024483:Vitamin K 3 / Q000633:toxicity*; D015262:Xenobiotics / Q000633:toxicity*
D018994:Myosin Light Chains; D015262:Xenobiotics; D024483:Vitamin K 3; D001151:Arsenic; D002118:Calcium