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Preparation of Rat Skeletal Muscle Homogenates for Nitrate and Nitrite Measurements
Published on: July 29, 2021
Understanding organic nitrates--a vein hope?
Mark R Miller1, Roger M Wadsworth
1Department of Cardiovascular Science, University of Edinburgh, Edinburgh, UK. mark.miller@ed.ac.uk
British Journal of Pharmacology
|July 28, 2009
Summary
Organic nitrate drugs like glyceryl trinitrate (GTN) treat angina by releasing nitric oxide (NO). Mitochondrial aldehyde dehydrogenase (mtALDH) activates GTN, but its complex role in tolerance remains under investigation.
Area of Science:
- Pharmacology
- Biochemistry
- Cardiovascular Medicine
Background:
- Organic nitrates, including glyceryl trinitrate (GTN), are effective anti-anginal medications due to their vasodilatory properties.
- The precise mechanism of intracellular nitric oxide (NO) delivery from organic nitrates is not fully elucidated.
- Mitochondrial aldehyde dehydrogenase (mtALDH) has been identified as a key enzyme in organic nitrate bioactivation.
Purpose of the Study:
- To investigate the role of mitochondrial aldehyde dehydrogenase (mtALDH) in the bioactivation of glyceryl trinitrate (GTN).
- To explore the relationship between mtALDH activity, nitric oxide (NO) generation, and the development of nitrate tolerance.
- To examine the influence of ascorbate deficiency on GTN responsiveness and nitrate tolerance.
Main Methods:
- Enzyme activity assays to measure mtALDH function.
- Assessment of GTN responsiveness in ascorbate-deficient guinea-pigs.
- Analysis of NO generation and oxygen-free radical production.
Main Results:
- mtALDH is crucial for the bioactivation of GTN, the primary organic nitrate used for angina.
- Nitrate tolerance is associated with reduced GTN bioactivation and/or increased oxygen-free radical formation.
- Ascorbate deficiency impaired GTN responsiveness but did not cause nitrate tolerance, showing distinct changes in mtALDH activity.
Conclusions:
- The intricate function of mtALDH is central to GTN activation and the formation of active NO species.
- mtALDH plays a critical role in the induction of nitrate tolerance, which can limit the clinical efficacy of organic nitrate drugs.
- Understanding mtALDH's complex role is key to optimizing organic nitrate therapy for angina.
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