Abstract
Chronic use of glyceryl trinitrate (GTN) is limited by serious side effects, such as tolerance and endothelial dysfunction of coronary and resistance arteries. Although GTN is used as a drug since more than 130 years, the mechanisms of the vasodilatory effects and of tolerance development to organic nitrates are still incompletely elucidated. New synthesized organic nitrates with and without antioxidant properties were characterized for their ex vivo tolerance profile, in order to investigate the oxidative stress hypothesis of nitrate tolerance. The organic nitrates studied showed different vasodilation and tolerance profiles, probably due to the ability or inability of the compounds to interact with the aldehyde dehydrogenase-2 enzyme (ALDH-2) involved in bioactivation. Furthermore, nitrooxy derivatives endowed with antioxidant properties did not determine the onset of tolerance, even if bioactivated by ALDH-2. The results of this study could be further evidence of the involvement of ALDH-2 in the development of nitrate tolerance. Moreover, the behavior of organic nitrates with antioxidant properties supports the hypothesis of the involvement of ROS in inactivating ALDH-2.
Highlights
Accepted: 14 January 2022Organic nitrates such as glyceryl trinitrate (GTN) are the most commonly adopted vasodilators in coronary artery diseases
Different enzymes have been implicated in the bioconversion of organic nitrates, in particular glutathione S-transferases, the cytochrome P450 system, xanthine oxidoreductase, and glyceraldehyde-3-phosphate dehydrogenase, recent evidence suggests a central role for mitochondrial lipoic acid-dependent aldehyde dehydrogenase (ALDH)-2 [4,5,6]
It has been reported that the GTN bioactivation catalyzed by aldehyde dehydrogenase-2 enzyme (ALDH-2) involves the oxidation of two vicinal cysteine residues, leading to the formation of a disulfide; this mechanism implicates the requirement of a reducing agent for sustained catalysis [7]
Summary
Accepted: 14 January 2022Organic nitrates such as glyceryl trinitrate (GTN) are the most commonly adopted vasodilators in coronary artery diseases. It has been reported that the GTN bioactivation catalyzed by ALDH-2 involves the oxidation of two vicinal cysteine residues, leading to the formation of a disulfide; this mechanism implicates the requirement of a reducing agent (such as lipoic acid) for sustained catalysis [7]. Organic nitrates are still among the most commonly prescribed medications for the treatment of angina pectoris and myocardial infarction, any hypothesis concerning the mechanism of action of these drugs must take into account the phenomenon of tolerance. The chronic efficacy of nitrates is blunted due to the development of nitrate tolerance and endothelial dysfunction [8].
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