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Updated: May 25, 2026
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Analytical Techniques for Assaying Nitric Oxide Bioactivity
Published on: June 18, 2012
Arginase II inhibition prevents nitrate tolerance
S M L Khong1, K L Andrews, N N Huynh
1Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
British Journal of Pharmacology
|February 1, 2012
Summary
Arginase II inhibition prevents nitrate tolerance by reducing reactive oxygen species (ROS) and endothelial nitric oxide synthase (eNOS) uncoupling. This finding offers a potential therapeutic strategy for improving nitrate efficacy.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Nitrate tolerance, a loss of vascular responsiveness, limits the therapeutic use of nitrates.
- Vascular superoxide, generated by uncoupled endothelial nitric oxide synthase (eNOS), is implicated in nitrate tolerance.
- Arginase competes with eNOS for L-arginine, potentially increasing reactive oxygen species (ROS) production.
Purpose of the Study:
- To investigate whether arginase inhibition can prevent or reduce nitrate tolerance.
- To explore the role of arginase II in the mechanisms underlying nitrate tolerance.
Main Methods:
- Vascular reactivity was assessed in mouse aorta using myography.
- eNOS uncoupling was evaluated by analyzing the eNOS monomer:dimer ratio.
- ROS levels were quantified using chemiluminescence assays.
Main Results:
- Arginase inhibition and arginase II knockout prevented nitrate tolerance in mouse aorta.
- Nitrate tolerance induction increased arginase activity and ROS production in wild-type mice.
- Arginase II deficiency or inhibition reduced eNOS uncoupling and ROS levels.
Conclusions:
- Arginase II plays a critical role in the development of nitrate tolerance.
- Inhibiting arginase II may be a viable strategy to overcome nitrate tolerance.
- Reduced eNOS uncoupling and ROS production are key mechanisms by which arginase inhibition prevents nitrate tolerance.
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