A hypothesis on the metabolism of glyceryl trinitrate in vascular endothelial cells

• Published in: Clinica chimica acta Vol. 313; no. 1; pp. 51 - 57
• Main Authors: Tian, Yaping, Zhang, Cuilan, Fang, Zhengyu, Betts, W.H
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Shannon Elsevier B.V 01.11.2001; Elsevier
• Subjects: Antianginal agents. Coronary vasodilator agents; Biological and medical sciences; Buffers; Cardiovascular system; Cells, Cultured; Culture Media; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Glyceryl trinitrate; Humans; Medical sciences; Metabolism; Nitrite; Nitrites - metabolism; Nitroglycerin - metabolism; Pharmacology. Drug treatments; Nitrite; Metabolism; Endothelial cells; Glyceryl trinitrate; Human; Metabolite; Nitric oxide; Nitrites; Nitroglycerin; Metabolic pathway; Mechanism of action; Vasodilation
• ISSN: 0009-8981; 1873-3492
• DOI: 10.1016/S0009-8981(01)00649-0

Background: Extensive research has been conducted regarding the mechanism of action of glyceryl trinitrate (GTN). It is currently believed that GTN undergoes a thiol-dependent metabolic pathway and releases its active metabolite, nitric oxide (NO) and/or S-nitrosothiols (R-SNO). This activates guanylyl cyclase (GC) leading to the formation of cGMP, which is responsible for the relaxation of vascular smooth muscles and the inhibition of platelet aggregation. The lack of knowledge as to the precise mechanism of GTN action and the modulation of its formation has limited the prevention of tolerance to GTN. Results: With cultured human vascular endothelial cells (EC), we showed that nitrite was first formed in endothelial cells whose concentration was dependent on reduced thiols. Cells preexposed to GTN significantly decreased the production of nitrite compared with cells that were not preexposed. Furthermore, we showed that thiols in cultured cells were oxidized during interaction with GTN, which correlated with the time of exposure to GTN. Conclusion: Nitrite is the first active intermediate of GTN metabolism in endothelial cells. The analysis of the changes of the blood nitrite and reduced thiols concentration is helpful for evaluating the vasodilatation activity of GTN during therapeutic treatments.