Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels

Hink, Ulrich; Daiber, Andreas; Kayhan, N; Trischler, Jordis; Kraatz, Catharina; Oelze, Matthias; Mollnau, Hanke; Wenzel, Philip; Vahl, Christian F.; Ho, Kwok Ki; Weiner, Henry; Münzel, Thomas

doi:10.1016/j.jacc.2007.08.031

Cited by 58 publications

(57 citation statements)

References 19 publications

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“…Among the various mechanisms that have been proposed to explain this nitrate tolerance (Fung, 2004;Mayer and Beretta, 2008), inactivation of ALDH2 (Chen et al, 2002) and superoxidemediated oxidation of GTN-derived NO (Mü nzel et al, 2005) are the most promising candidates at present. Denitration of GTN results in mechanism-based inactivation of ALDH2 (Beretta et al, 2008b), GTN-tolerant blood vessels exhibit markedly reduced ALDH2 activity (Sage et al, 2000;DiFabio et al, 2003;Sydow et al, 2004;Hink et al, 2007;Wenzl et al, 2009b), and ALDH2(Ϫ/Ϫ) mice do not become tolerant (Chen et al, 2005). Taken together, these results suggest that vascular tolerance to GTN is explained by inactivation of ALDH2.…”

Section: Introductionmentioning

confidence: 81%

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

et al. 2010

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Mitochondrial aldehyde dehydrogenase (ALDH2) contributes to vascular bioactivation of the antianginal drugs nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN), resulting in cGMP-mediated vasodilation. Although continuous treatment with GTN results in the loss of efficacy that is presumably caused by inactivation of ALDH2, PETN does not induce vascular tolerance. To clarify the mechanisms underlying the distinct pharmacological profiles of GTN and PETN, bioactivation of the nitrates was studied with aortas isolated from ALDH2-deficient and nitrate-tolerant mice, isolated mitochondria, and purified ALDH2. Pharmacological inhibition or gene deletion of ALDH2 attenuated vasodilation to both GTN and PETN to virtually the same degree as long-term treatment with GTN, whereas treatment with PETN did not cause tolerance. Purified ALDH2 catalyzed bioactivation of PETN, assayed as activation of soluble guanylate cyclase (sGC) and formation of nitric oxide (NO). The EC 50 value of PETN for sGC activation was 2.2 Ϯ 0.5 M. Denitration of PETN to pentaerythrityl trinitrate was catalyzed by ALDH2 with a specific activity of 9.6 Ϯ 0.8 nmol ⅐ min Ϫ1 ⅐ mg Ϫ1 and a very low apparent affinity of 94.7 Ϯ 7.4 M. In contrast to GTN, PETN did not cause significant inactivation of ALDH2. Our data suggest that ALDH2 catalyzes bioconversion of PETN in two distinct reactions. Besides the major denitration pathway, which occurs only at high PETN concentrations, a minor high-affinity pathway may reflect vascular bioactivation of the nitrate yielding NO. The very low rate of ALDH2 inactivation, presumably as a result of low affinity of the denitration pathway, may at least partially explain why PETN does not induce vascular tolerance.

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Section: Introductionmentioning

confidence: 81%

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

et al. 2010

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“…Whatever the nature of this chemical species, these findings found rapid human translation. For instance, incubation of human vessels with an ALDH-2 inhibitor recapitulated the abnormalities associated with the development of tolerance, 32 ( Figure 5) and a loss-of-function mutation of ALDH-2 particularly frequent in Eastern Asia and Eastern Europe was found to be associated with impaired GTN metabolism and reduced responsiveness to GTN. 33 …”

Section: Aldehyde Dehydrogenase the Enzyme That Metabolizes Alcoholmentioning

confidence: 93%

“…Subsequently, we demonstrated that GTN treatment stimulates the vascular (and particularly endothelial) production of peroxynitrite, a highly reactive intermediate generated from the rapid, diffusion-limited reaction of NO with O 2 ·Ϫ . 32,46 Evidence of GTN-induced increased ROS production in humans was then obtained ex vivo in arterial segments and in blood or platelets taken from patients rendered tolerant to GTN. 19,39,48,49 GTN tolerance was also associated with increased markers of free radical-induced lipid peroxidation such as cytotoxic aldehydes and isoprostanes 50 and esterified 8-epi-PGF 2␣ 51 and with a mild reduction in the responsiveness to the NO donor sodium nitroprusside in healthy volunteers, 4 which might also be compatible with ROSmediated interference with NO signaling.…”

Section: Does Oxidative Stress Account For Nitratementioning

confidence: 99%

Nitrate Therapy

2011

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A lthough the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion 1 as well as specific vascular changes such as increased vascular superoxide (O 2 ·Ϫ ) production, 2 increased sensitivity to vasoconstrictors, 3 and decreased responsiveness to nitric oxide (NO) donors 4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focused on the concept that an inappropriate production of reactive oxygen species (ROS), an impairment in the scavenging of these mediators (Figure 1), or both might have a crucial mechanistic importance in all these modifications. 6,7 Independently of the role of ROS in tolerance, the possibility that nitrate-induced oxidative stress might affect patients' prognosis has important implications, and the observation that long-term therapy with most of the drugs in this class causes endothelial dysfunction, the prognostic significance of which is well accepted in patients with coronary artery disease, hypertension, and heart failure, 8 should not be taken as an academic curiosity.Beyond these as-yet insufficiently investigated prognostic implications, recognition of the role of ROS suggests that a number of interventions thought to interfere with the vascular redox balance might also retard or prevent the development of nitrate tolerance and nitrate-induced side effects. Evidence that therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin-1 receptor blockers, certain ␤-blockers, statins, and vitamins such as folic acid or vitamin C beneficially influence nitrate tolerance and glyceryl trinitrate (GTN)-induced endothelial dysfunction suggests that nitrate therapy might have profoundly different implications since these therapies have become diffusely available. In addition, the recognition of important differences in the mechanisms triggered by different nitrates should also be attributed clinical relevance, and evidence suggests that, rather than the generic nitrate tolerance, more specific expressions (GTN tolerance, isosorbide mononitrate [ISMN] tolerance, etc) should be used. 9 This review summarizes the current concepts underlying tolerance and endothelial dysfunction in response to longterm therapy with different nitrates and addresses the question of whether the use of these drugs remains indicated despite these side effects. The Hemodynamic Effects of NitratesVenous capacitance vessels, large and medium-sized coronary arteries, and collateral vessels are most sensitive to GTN, whereas coronary and peripheral arterioles with a diameter Ͻ100 m are relatively more resistant. In the setting of stable angina, the preferential venodilatation induced by antiischemic doses of GTN results in venous pooling an...

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“…That is, it is speculated that the activity and/or expression of aldehyde dehydrogenase (ALDH-2), a major enzyme responsible for nitroglycerin bioactivation, was decreased by pretreatment with nitroglycerin. In this regard, the decreased activity and expression of this enzyme in human vessels have been demonstrated to be induced by in vivo treatment with nitroglycerin (Hink et al 2007). Consequently, it is thought that the nitrate tolerance observed in the present study overlaps with, at least partially, that in the body.…”

Section: Discussionmentioning

confidence: 99%

Vasorelaxing effects of the soluble guanylyl cyclase activator BAY 60-2770 in nitrate-tolerant monkey and canine coronary arteries

Tawa

Shimosato

Iwasaki

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Nitrate tolerance is an important problem in the treatment of ischemic heart diseases. The present study investigated whether or not a soluble guanylyl cyclase (sGC) activator can be used as a coronary vasodilator under nitrate-tolerant conditions. Helically cut strips of endothelium-denuded monkey and canine coronary arteries were suspended in organ chambers for isometric tension recording. Nitrate tolerance was induced by a 1-h treatment with nitroglycerin (0.1 mM) followed by 1-h washout of the agent. Control strips were not exposed previously to nitroglycerin, but otherwise were treated identically. The relaxant response to nitroglycerin was dramatically impaired by previous exposure to the drug for 1 h in either monkey or canine coronary arteries, indicating the development of nitrate tolerance. In contrast, development of nitrate tolerance did not affect the relaxant potency and efficacy of the sGC activator BAY 60-2770 in either the monkey or canine coronary arteries. These findings suggest that it may be possible to use sGC activators as substitute drugs for nitroglycerin if tolerance is developed during the treatment of ischemic heart diseases.

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Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels

Abstract: Long-term GTN treatment induces tolerance and endothelial dysfunction in human vessels, associated with an inhibition and down-regulation of vascular ALDH-2. Thus, these findings extend results of previous animal studies to humans.

Cited by 58 publications

References 19 publications

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

Bioactivation of Pentaerythrityl Tetranitrate by Mitochondrial Aldehyde Dehydrogenase

Nitrate Therapy

Vasorelaxing effects of the soluble guanylyl cyclase activator BAY 60-2770 in nitrate-tolerant monkey and canine coronary arteries

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