Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study

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.

A Model to Study the Inhibition of Arginase II with Noscapine & Its Derivatives

Background and Purpose Nitrate tolerance can be explained based on the reduction of the vessel responsiveness and the same is used for endogenous vasodilator Nitric Oxide (NO). There are some limitations for the treatment of ischaemia, angina etc. and it attracted the scientists and researchers. The location of arginase II is endothelial cells in mitochondria and it is used to change the potency of endothelial nitric oxide synthase.

Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase activity? A contribution to the ongoing discussion

The aim of the study presented here was an attempt to answer the question posed in the title: Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase (ALDH) activity? Here, we investigated the effect of administration (separately or jointly) of lipoic acid (LA), nitroglycerin (GTN), and disulfiram (DSF; an irreversible in vivo inhibitor of all ALDH isozymes (including ALDH2)), on the development of tolerance to GTN. We also assessed the total activity of ALDH in the rat liver homogenates. Our data revealed that not only DSF and GTN inhibited the total ALDH activity in the rat liver, but LA also proved to be an inhibitor of this enzyme. At the same time, the obtained results demonstrated that the GTN tolerance did not develop in GTN, DSF and LA jointly treated rats, but did develop in GTN and DSF jointly treated rats. This means that the ability of LA to prevent GTN tolerance is not associated with the total ALDH activity in the rat liver. In this context, the fact that animals jointly receiving GTN and DSF developed tolerance to GTN, and in animals that in addition to GTN and DSF also received LA such tolerance did not develop, is – in our opinion – a sufficient premise to conclude that the nitrate tolerance certainly is not caused by a decrease in the activity of any of the ALDH isoenzymes present in the rat liver, including ALDH2. However, many questions still await an answer, including the basic one: What is the mechanism of tolerance to nitroglycerin?

Kinetic Analysis on Decomposition of Pentaerythrityl Tetranitrate under Influence of Thiols

Pentaerythrityl tetranitrate (PETN) is an organic nitrate compound used in the therapy asgeneral vasodilator in the treatment of angina pectoris. PETN acts as prodrug for nitric oxideas active component. However, in clinical association, it is known a decreased ability oforganic nitrate to do chemical reduction, which is metabolic tolerance, by upregulation inendogenic thiol system. It has been proved that supplementation of thiol is able to overcometolerance to nitrate, nevertheless there is no comprehensive reports on interaction betweenorganic nitrate and thiol compounds. The goal of this research is to study decompositionreaction kinetic of PETN under influence N-acetyl cysteine (NAC) and thiosalicylic acid(TSA) as thiol compounds, in the physiological condition. PETN as tracing compound weremonitored by chromatographic system, with ratio of thiols used was equal, doubled, fivetimes, and ten times folds. Data were analyzed kinetically by using math equation for reactionorder 1, 2, and composite order 1 (equivalence). The result showed the linearity values onkinetic derivative, where correlation coefficient, r, is higher than 0.9 (r ≥ 0.9) for compositeorder 1. The result will give scientific contribution about tolerance phenomena in organicnitrate, particularly in the role of thiol compound to overcome nitrate tolerance.