Oxidative Stress and Mitochondrial Aldehyde Dehydrogenase Activity: A Comparison of Pentaerythritol Tetranitrate with Other Organic Nitrates

Abstract

Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN-and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations Ͼ1 M. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.Organic nitrates such as nitroglycerin (glyceryl trinitrate; GTN) are widely used in the therapy of cardiovascular diseases such as stable and unstable angina (Abrams, 1995).The anti-ischemic effects of organic nitrates are largely caused by venous and coronary artery dilation as well as the improvement of collateral blood flow, which all decrease myocardial oxygen consumption. Their use, however, is limited because of the rapid development of tolerance and crosstolerance characterized by decreased sensitivity of the vasculature to the organic nitrates and to endothelium-dependent vasodilators, respectively (Mangione and Glasser,

Decrease in endogenous CGRP release in nitroglycerin tolerance: Role of ALDH-2

“…There is evidence that oxidants can inactivate ALDH-2 directly and induce nitrate tolerance Wenzel et al, 2007). Oxidative stress may contribute directly to nitroglycerin tolerance, either by oxidative inhibition of ALDH-2 or perhaps by oxidizing key enzyme cofactors (Chen et al, 2002;Sydow et al, 2004;Daiber et al, 2004;Munzel et al, 2005). The present study confirmed previous observations that pretreatment of the isolated rat thoracic aorta with ALDH-2 inhibitors significantly attenuated the vasodilation and depressor effect of nitroglycerin (Chen et al, 2002;Sydow et al, 2004).…”

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

“…Proposed mechanisms of tolerance include: (1) depletion of critical sulfhydryl groups [5], (2) desensitization of guanylyl cyclase [6], (3) impaired bioconversion of nitrates leading to diminished NO-release [7], (4) reduced generation of NO from nitrates [8], (5) increased activity of the cyclic GMP phosphodiesterase, which decreases cyclic GMP levels [9] and (6) a free radical hypothesis proposing increased oxidant stress [10,11]. Nitroglycerininduced reactive oxygen species also inhibit the activation of nitroglycerin by thiol oxidation of mitochondrial aldehyde dehydrogenase which might explain why nitroglycerin elicits mitochondrial superoxide formation and nitrate tolerance [12].…”

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

“…In addition, a key enzyme involvement of nitroglycerin and nitrates biotransformation, namely the mitochondrial aldehyde dehydrogenase (ALDH 2), is inhibited by reactive oxygen species (ROS) which in addition, can degrade nitric oxide (Wenzel et al, , 2009bDaiber et al, 2004Daiber et al, , 2009bSydow et al, 2004). Therefore, it would be interesting to study the benefit of antioxidants in preventing nitrate tolerance development.…”

“…In the current state of knowledge, oxidative stress is a major cause of this phenomenon (Fadel et al, 2012;Oelze et al, 2010;Daiber et al, 2004;Mollnau et al, 2006). Thus, our hypothesis derives from the antioxidant capacity of compounds to reduce or prevent vascular tolerance to nitrates, by reducing oxidative stress.…”