Aldehyde Dehydrogenase 2 Plays a Role in the Bioactivation of Nitroglycerin in Humans

Abstract

Objective-Nitrates are used widely in clinical practice. However, the mechanism underlying the bioactivation of nitrates to release NO remains unclear. Recent animal data suggest that mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in nitrate bioactivation, but its role in humans is not known. We investigated the role of ALDH2 in the vascular effects of nitroglycerin (NTG) Key Words: nitroglycerin Ⅲ nitric oxide Ⅲ nitrates Ⅲ blood flow Ⅲ vasodilation N itrates have been used for Ͼ100 years in the treatment of angina, heart failure, and hypertension. Several different forms are in clinical use, including nitroglycerin (NTG), isosorbide mononitrate, and isosorbide dinitrate. Nevertheless, they all induce vasodilatation via NO release and display tolerance with continued use. The exact mechanism of bioactivation of nitrates is unclear, but several candidate enzymes have been suggested, including glutathione-Stransferase, 1 cytochrome p450 reductase, 2 cytochrome p450, 3 old yellow enzyme, 4 and xanthine oxidoreductase. 5 Recent work by Chen et al identified mitochondrial aldehyde dehydrogenase (ALDH2) as an important enzyme involved in the bioactivation of nitrates in animals and suggested that nitrate tolerance may be caused by ALDH2 inhibition. 6 Although the role of ALDH2 in the bioactivation of nitrates has been confirmed by subsequent in vitro and in vivo animal studies, 7-9 its role in humans remains unclear. Interestingly, a common glu504lys point mutation in the ALDH2 gene is present among people of East Asian ethnic origin and causes a low-activity form of the enzyme, with heterozygotes having Ϸ6.25% of normal ALDH2 enzyme activity 10 and homozygotes 0%. The mutation is associated with flushing after alcohol ingestion, but its effect on the bioactivation of nitrates has not been investigated.To investigate the hypothesis that ALDH2 is involved in the bioactivation of nitrates in humans, we designed 2 clinical studies. In the first study, the ALDH2 inhibitor disulfiram was administered to healthy volunteers, and the vasodilatory response to NTG was measured before and after inhibition of the enzyme. In the second study, the response to NTG in a group of healthy volunteers heterozygous or homozygous for the ALDH2 mutation was compared with that in homozygous wild-type control volunteers. Venous occlusion plethysmography was used to measure forearm blood flow (FBF) responses to intra-arterial infusions of NTG in both studies. The responses to 2 other control vasodilators that do not undergo the same mechanism of bioactivation as NTG, sodium nitroprusside (SNP), which acts via direct release of NO, and verapamil, a calcium channel blocker, acting via an NO-independent mechanism, were also measured. Methods SubjectsSubjects were drawn from a community-based volunteer register, and all were free from cardiovascular disease and were nonsmokers. Individuals with hypertension, diabetes mellitus, hypercholesterolemia, or those receiving medication were excluded. All subjects were genotyped for th...

The Glu504Lys Polymorphism of Aldehyde Dehydrogenase 2 Contributes to Development of Coronary Artery Disease

“…However, after taking sublingual nitroglycerine, the degree of brachial artery dilatation in patients with the ALDH2 *504Lys allele was significantly lower than in those with the wild-type (Xu et al 2011). These results demonstrate that the ALDH2 *504Lys allele exerts a significant effect on non-endothelium-dependent vasodilation and an insignificant effect on endothelium-dependent vasodilation, which is consistent with previous studies (Zhang et al 2004;Mackenzie et al 2005). Previous studies have confirmed that coronary spasm is significantly correlated with damaged endothelium-but not with non-endotheliumdependent vasodilation.…”

“…Recent studies have found that mitochondrial ALDH2 is also a critical enzyme for converting nitroglycerine into nitric oxide (Li et al 2006). ALDH2 inhibition can significantly reduce the vasodilatory effects of nitroglycerine (Mackenzie et al 2005;Daiber et al 2009). Another canine study also confirmed that the inhibition of ALDH2 activity can significantly reduce the dilation of canine coronary vessels (Zhang et al 2004).…”

Nitrate Therapy

“…73 In addition, despite showing a markedly reduced GTN-induced vasodilation in carriers of ALDH-2 polymorphisms and after ALDH-2 inhibition, human studies suggested that this enzyme accounts for only a half of the total bioactivation of GTN. 33 Challenging the role of ROS-induced abnormalities, Sage et al 49 reported an impaired biotransformation of GTN in venous tissue from patients treated with GTN but no cross-resistance to other NO donors and to a calcium ionophore; in this study, although the bioavailability of superoxide anion was increased in arterial segments from the same patients, short-term exposure to oxidative stress did not change GTN responsiveness. Further emphasizing the complexity of the mechanisms underlying GTN tolerance, in another study, folic acid preserved arterial, but not venous, responsiveness to sublingual GTN, 74 suggesting the existence of different mechanisms across different vascular beds.…”

“…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 …”

Nitroxyl Anion Donor, Angeli’s Salt, Does Not Develop Tolerance in Rat Isolated Aortae

“…38,39 Indeed, in an investigation into the role of ALDH-2 in the biotransformation of GTN in humans in vivo, complete ALDH-2 inhibition by disulfiram therapy only resulted in a 33% reduction in GTN responses. 40 Recently, altered phosphodiesterase 5 activity was also implicated in the development of GTN tolerance in veins. 41 In striking contrast to our findings with AS, pretreatment of vessels with DEA/NO caused marked cross-tolerance to GTN.…”