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Measurement of Cyclic Guanosine Monophosphate (cGMP) in Solid Tissues using Competitive Enzyme-Linked Immunosorbent Assay (ELISA)
Published on: July 3, 2025
Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in
12nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Abstract:
Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100mg/kg/d for 3.5days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5mg/kg/d) or BAY 41-8543 (1 and 5mg/kg/d) for 6days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial dysfunction and nitrate tolerance, corrected the decrease in aortic nitric oxide levels, improved the cGMP dependent activation of protein kinase I in aortic tissue and reduced vascular, cardiac and whole blood oxidative stress (fluorescence and chemiluminescence assays; 3-nitrotyrosine staining). In contrast to BAY 41-8543, the vasodilator potency of BAY 60-2770 was not impaired in isolated aortic ring segments from nitrate tolerant rats. sGC activator therapy improves partially the adverse effects of nitroglycerin therapy whereas sGC stimulation has only minor beneficial effects pointing to a nitroglycerin-dependent sGC oxidation/inactivation mechanism contributing to nitrate tolerance.
Insights
Soluble guanylyl cyclase (sGC) activator therapy partially improved adverse effects of chronic nitroglycerin (GTN) treatment, including endothelial dysfunction and nitrate tolerance. sGC stimulation showed minimal benefits, suggesting GTN-induced sGC oxidation contributes to tolerance.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Nitric Oxide Signaling
Background:
- Chronic nitroglycerin (GTN) therapy for anti-ischemia causes nitrate tolerance and endothelial dysfunction.
- These side effects may stem from desensitization or oxidation of soluble guanylyl cyclase (sGC).
Purpose of the Study:
- To investigate the effects of sGC activator BAY 60-2770 and sGC stimulator BAY 41-8543 on GTN-induced side effects.
- To elucidate the role of sGC oxidation in nitrate tolerance.
Main Methods:
- Male Wistar rats received chronic GTN treatment.
- Rats were co-treated with either BAY 60-2770 (an sGC activator) or BAY 41-8543 (an sGC stimulator).
- Endothelial function, nitrate tolerance, nitric oxide levels, cGMP-dependent protein kinase I activation, and oxidative stress markers were assessed.
Main Results:
- BAY 60-2770 therapy improved GTN-induced endothelial dysfunction and nitrate tolerance.
- BAY 60-2770 corrected decreased aortic nitric oxide levels and reduced oxidative stress.
- BAY 41-8543 showed only minor beneficial effects, and its vasodilator potency was impaired in nitrate-tolerant rats, unlike BAY 60-2770.
Conclusions:
- sGC activator therapy offers partial protection against adverse effects of chronic GTN therapy.
- sGC stimulation has limited benefits, supporting a mechanism involving GTN-dependent sGC oxidation/inactivation in nitrate tolerance.
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