Glyceryl Trinitrate: History, Mystery, and Alcohol Intolerance

Abstract

Glyceryl trinitrate (GTN) is one of the earliest known treatments for angina with a fascinating history that bridges three centuries. However, despite its central role in the nitric oxide (NO) story as a NO-donating compound, establishing the precise mechanism of how GTN exerts its medicinal benefit has proven to be far more difficult. This review brings together the explosive and vasodilatory nature of this three-carbon molecule while providing an update on the likely in vivo pathways through which GTN, and the rest of the organic nitrate family, release NO, nitrite, or a combination of both, while also trying to explain nitrate tolerance. Over the last 20 years the alcohol detoxification enzyme, aldehyde dehydrogenase (ALDH), has undoubtedly emerged as the front runner to explaining GTN’s bioactivation. This is best illustrated by reduced GTN efficacy in subjects carrying the single point mutation (Glu504Lys) in ALDH, which is also responsible for alcohol intolerance, as characterized by flushing. While these findings are significant for anyone following the GTN story, they appear particularly relevant for healthcare professionals, and especially so, if administering GTN to patients as an emergency treatment. In short, although the GTN puzzle has not been fully solved, clinical study data continue to cement the importance of ALDH, as uncovered in 2002, as a key GTN activator.

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“…The mechanisms may involve factors such as sulfhydryl group depletion and down‐regulation of enzymes responsible for bioactivation, etc. [ 101 ] (4)N‐diazeniumdiolate (NONOate) encompasses a class of compounds containing the structure R 1 R 2 N‐(NO‐)‐N = O. DEA/NO , the NO admixture of diethylamine, was the first reported N‐diazeniumdiolate in the middle of the last century. [ 102 ] In contrast to the aforementioned NO donors, NONOates spontaneously dissociate and release two molecules of NO.…”

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“…In the meantime, the development of homeopathic medicine (based on the principle of cure by the similitude “like cures like”) was the cornerstone for the entry of NTG in the Pharmacopoeia and Medicine. In parallel, Brunton discovered the ability of a nitric-containing compound, amyl nitrite, to lower blood pressure and relieve anginal pain [ 1 , 2 ]. Based on all these observations, William Murrel successfully treated angina pectoris for the first time with NTG in 1878.…”

Synthesis and Vasorelaxant Activity of Nitrate−Coumarin Derivatives

“…Other organic nitrate esters used in therapeutics are isosorbide mononitrate, isosorbide dinitrate or pentaerythrityl tetranitrate. Although it has been accepted for years that the generation of NO is involved, there are still many controversies about the mechanism of the vasodilator action of these molecules [5,6] . As for sodium nitroprusside (SNP), a S−nitrosothiol composed of ferrous iron complexed with nitric oxide (NO) and five cyanide ions (Figure 1), used in therapeutics as a vasodilator in hypertensive crisis and cardiovascular emergencies.…”

“…Although it has been accepted for years that the generation of NO is involved, there are still many controversies about the mechanism of the vasodilator action of these molecules. [ 5 , 6 ] As for sodium nitroprusside (SNP), a S−nitrosothiol composed of ferrous iron complexed with nitric oxide (NO) and five cyanide ions (Figure 1 ), used in therapeutics as a vasodilator in hypertensive crisis and cardiovascular emergencies. SNP ability to produce NO depends on the oxidation of sulfhydryl residues (SH) present in sGC.…”