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Possible involvement of nitroglycerin converting step in nitroglycerin tolerance
K Hasegawa1, T Taniguchi, K Takakura
1Department of Anesthesiology and Reanimatology, School of Medicine, Fukui Medical University, Matsuoka, Japan.
Life Sciences
|June 22, 1999
Summary
Nitroglycerin tolerance involves reduced nitric oxide (NO) release from nitroglycerin (GTN). This occurs because prior NO exposure inhibits the GTN-converting step, diminishing vascular smooth muscle relaxation.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Biochemistry
Background:
- Nitroglycerin (GTN) induces vascular smooth muscle relaxation via nitric oxide (NO) release.
- Tolerance to GTN, a marked attenuation of its effects, develops after prolonged or repeated exposure.
- Understanding GTN tolerance mechanisms is crucial for effective cardiovascular therapy.
Purpose of the Study:
- To investigate the mechanisms underlying nitroglycerin (GTN) tolerance.
- To examine the role of nitric oxide (NO) in GTN tolerance using exogenous and endogenous sources in rat aorta.
- To elucidate the specific pathways affected by GTN pre-exposure and lipopolysaccharide (LPS) treatment.
Main Methods:
- Utilized endothelium-denuded rat aortic strips for relaxation studies.
- Administered GTN and sodium nitroprusside (SNP) to assess pre-exposure effects on relaxation responses.
- Investigated the impact of lipopolysaccharide (LPS) +/- L-arginine preincubation on GTN-induced relaxation, cGMP production, and nitrite/nitrate formation.
- Evaluated the role of cycloheximide and N(G)-nitro-L-arginine in modulating LPS-induced tolerance.
Main Results:
- Preceding exposure to GTN or SNP attenuated GTN-induced relaxation in rat aortic strips.
- SNP-induced relaxation remained unaffected by GTN or SNP pre-exposure, suggesting a specific mechanism for GTN tolerance.
- LPS preincubation attenuated GTN-induced relaxation, cGMP production, and nitrite/nitrate formation.
- The attenuating effect of LPS was abolished by co-incubation with cycloheximide or N(G)-nitro-L-arginine, indicating involvement of protein synthesis and NO pathways.
Conclusions:
- GTN tolerance is primarily linked to a reduced release of NO from GTN.
- This reduction is attributed to the inhibition of a GTN-converting step, triggered by prior exposure to NO.
- The findings highlight the complex interplay between NO signaling and GTN metabolism in the development of tolerance.