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New approaches to overcome tolerance to nitrates
Michael Schwemmer1, Eberhard Bassenge
1Albert-Ludwigs University, Institute of Applied Physiology, Hermann-Herder-Str. 7, 79104 Freiburg, Germany.
Cardiovascular Drugs and Therapy
|September 17, 2003
Summary
Tolerance to nitric oxide (NO) donors, like nitroglycerin, can be overcome. Antioxidants prevent and reverse this tolerance by targeting oxidative stress, suggesting a key role for redox balance in treatment.
Area of Science:
- Pharmacology
- Cardiovascular Science
- Biochemistry
Background:
- Nitric oxide (NO) donors are crucial for vasodilation but can induce tolerance, limiting their efficacy.
- The mechanisms underlying tolerance to NO-donors, including tachyphylaxis, are complex and involve various cellular pathways.
- Reactive oxygen species (ROS) generation has been implicated in the development of tolerance to nitrovasodilators.
Purpose of the Study:
- To analyze the induction of tachyphylaxis and tolerance to exogenous NO-donors across various experimental models.
- To investigate methods for circumventing or reversing tolerance to NO-donors.
- To determine the role of ROS in nitrovasodilator tolerance and explore antioxidant-based interventions.
Main Methods:
- Experiments were conducted using isolated cells (smooth muscle, endothelium, platelets), perfused hearts, in vivo animal models, and human subjects.
- Different nitrovasodilators, including PETN and GTN, were tested for their rates of tolerance and ROS generation.
- The efficacy of antioxidant supplementation (e.g., SOD, vitamin C, DMSO) and other modulators was evaluated in preventing and reversing tolerance.
Main Results:
- Nitrovasodilators exhibited varying rates and magnitudes of tolerance and ROS generation, with PETN showing the lowest and GTN the highest.
- Changes in ROS production in isolated cells mirrored those in vascular smooth muscle, endothelium, and platelets, validating platelets as marker cells.
- Antioxidant supplementation effectively suppressed or avoided tachyphylaxis and reversed established tolerance in all tested models, including humans.
Conclusions:
- ROS generation is a primary driver of nitrovasodilator tolerance, outweighing other factors like sympathetic activity or changes in intracellular signaling pathways.
- Platelets can serve as reliable biomarkers for assessing tolerance induction and oxidant stress associated with nitrate therapy.
- Targeting redox potential and antioxidant capacity is a promising strategy for managing and preventing tolerance to NO-donors in clinical settings.