Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans

Isla S. Mackenzie (Lead / Corresponding author), Kaisa M. Maki-Petaja, Carmel M. McEniery, Yi Ping Bao, Sharon M. Wallace, Joseph Cheriyan, Sue Monteith, Morris J. Brown, Ian B. Wilkinson

Research output: Contribution to journalArticle

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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) in humans in vivo. Methods and Results - Forearm blood flow (FBF) responses to intra-arterial infusions of NTG, sodium nitroprusside (SNP), and verapamil were measured in 12 healthy volunteers before and after ALDH2 inhibition by disulfiram. All drugs caused a dose-dependent vasodilatation. However, only the response to NTG was significantly reduced after disulfiram therapy (33% reduction in area under the curve [AUC]; P=0.002). Separately, 11 subjects of East Asian origin, with the loss-of-function glu5041ys mutation in the ALDH2 gene, received intra-arterial NTG, SNP, and verapamil. Only the FBF response to NTG was lower in the volunteers with the glu5041ys mutation compared with East Asian and non-Asian wild-type control subjects (40% reduction in AUC; P=0.02). Conclusions - The findings suggest that ALDH2 is involved in the bioactivation of NTG in humans in vivo but accounts for less than half of the total bioactivation. This may be of clinical importance in patients with mutations in the ALDH2 gene and in those taking drugs that inhibit ALDH2.

Original languageEnglish
Pages (from-to)1891-1895
Number of pages5
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume25
Issue number9
DOIs
Publication statusPublished - 1 Sep 2005

Fingerprint

Aldehyde Dehydrogenase
Nitroglycerin
Nitrates
Disulfiram
Nitroprusside
Verapamil
Forearm
Mutation
Area Under Curve
Intra Arterial Infusions
Vasodilation
Pharmaceutical Preparations
Genes
Blood Vessels
Volunteers
Healthy Volunteers

Keywords

  • Blood flow
  • Nitrates
  • Nitric oxide
  • Nitroglycerin
  • Vasodilation

Cite this

Mackenzie, Isla S. ; Maki-Petaja, Kaisa M. ; McEniery, Carmel M. ; Bao, Yi Ping ; Wallace, Sharon M. ; Cheriyan, Joseph ; Monteith, Sue ; Brown, Morris J. ; Wilkinson, Ian B. / Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2005 ; Vol. 25, No. 9. pp. 1891-1895.
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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) in humans in vivo. Methods and Results - Forearm blood flow (FBF) responses to intra-arterial infusions of NTG, sodium nitroprusside (SNP), and verapamil were measured in 12 healthy volunteers before and after ALDH2 inhibition by disulfiram. All drugs caused a dose-dependent vasodilatation. However, only the response to NTG was significantly reduced after disulfiram therapy (33{\%} reduction in area under the curve [AUC]; P=0.002). Separately, 11 subjects of East Asian origin, with the loss-of-function glu5041ys mutation in the ALDH2 gene, received intra-arterial NTG, SNP, and verapamil. Only the FBF response to NTG was lower in the volunteers with the glu5041ys mutation compared with East Asian and non-Asian wild-type control subjects (40{\%} reduction in AUC; P=0.02). Conclusions - The findings suggest that ALDH2 is involved in the bioactivation of NTG in humans in vivo but accounts for less than half of the total bioactivation. This may be of clinical importance in patients with mutations in the ALDH2 gene and in those taking drugs that inhibit ALDH2.",
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Mackenzie, IS, Maki-Petaja, KM, McEniery, CM, Bao, YP, Wallace, SM, Cheriyan, J, Monteith, S, Brown, MJ & Wilkinson, IB 2005, 'Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 9, pp. 1891-1895. https://doi.org/10.1161/01.ATV.0000179599.71086.89

Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans. / Mackenzie, Isla S. (Lead / Corresponding author); Maki-Petaja, Kaisa M.; McEniery, Carmel M.; Bao, Yi Ping; Wallace, Sharon M.; Cheriyan, Joseph; Monteith, Sue; Brown, Morris J.; Wilkinson, Ian B.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 25, No. 9, 01.09.2005, p. 1891-1895.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aldehyde dehydrogenase 2 plays a role in the bioactivation of nitroglycerin in humans

AU - Mackenzie, Isla S.

AU - Maki-Petaja, Kaisa M.

AU - McEniery, Carmel M.

AU - Bao, Yi Ping

AU - Wallace, Sharon M.

AU - Cheriyan, Joseph

AU - Monteith, Sue

AU - Brown, Morris J.

AU - Wilkinson, Ian B.

PY - 2005/9/1

Y1 - 2005/9/1

N2 - 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) in humans in vivo. Methods and Results - Forearm blood flow (FBF) responses to intra-arterial infusions of NTG, sodium nitroprusside (SNP), and verapamil were measured in 12 healthy volunteers before and after ALDH2 inhibition by disulfiram. All drugs caused a dose-dependent vasodilatation. However, only the response to NTG was significantly reduced after disulfiram therapy (33% reduction in area under the curve [AUC]; P=0.002). Separately, 11 subjects of East Asian origin, with the loss-of-function glu5041ys mutation in the ALDH2 gene, received intra-arterial NTG, SNP, and verapamil. Only the FBF response to NTG was lower in the volunteers with the glu5041ys mutation compared with East Asian and non-Asian wild-type control subjects (40% reduction in AUC; P=0.02). Conclusions - The findings suggest that ALDH2 is involved in the bioactivation of NTG in humans in vivo but accounts for less than half of the total bioactivation. This may be of clinical importance in patients with mutations in the ALDH2 gene and in those taking drugs that inhibit ALDH2.

AB - 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) in humans in vivo. Methods and Results - Forearm blood flow (FBF) responses to intra-arterial infusions of NTG, sodium nitroprusside (SNP), and verapamil were measured in 12 healthy volunteers before and after ALDH2 inhibition by disulfiram. All drugs caused a dose-dependent vasodilatation. However, only the response to NTG was significantly reduced after disulfiram therapy (33% reduction in area under the curve [AUC]; P=0.002). Separately, 11 subjects of East Asian origin, with the loss-of-function glu5041ys mutation in the ALDH2 gene, received intra-arterial NTG, SNP, and verapamil. Only the FBF response to NTG was lower in the volunteers with the glu5041ys mutation compared with East Asian and non-Asian wild-type control subjects (40% reduction in AUC; P=0.02). Conclusions - The findings suggest that ALDH2 is involved in the bioactivation of NTG in humans in vivo but accounts for less than half of the total bioactivation. This may be of clinical importance in patients with mutations in the ALDH2 gene and in those taking drugs that inhibit ALDH2.

KW - Blood flow

KW - Nitrates

KW - Nitric oxide

KW - Nitroglycerin

KW - Vasodilation

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