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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1891.)
© 2005 American Heart Association, Inc.

Vascular Biology

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

Isla S. Mackenzie; Kaisa M. Maki-Petaja; Carmel M. McEniery; Yi Ping Bao; Sharon M. Wallace; Joseph Cheriyan; Sue Monteith; Morris J. Brown; Ian B. Wilkinson

From the Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK.

Correspondence to Dr Isla S. Mackenzie, Clinical Pharmacology Unit Box 110, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail ism22{at}cam.ac.uk

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 glu504lys 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 glu504lys 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.

This study investigates the role of aldehyde dehydrogenase type 2 (ALDH2) in the bioactivation of nitrates in humans. We show that genetic and pharmacological reduction of ALDH2 activity decreases in vivo vascular responses to nitroglycerin, suggesting that ALDH2 is a mediator of the bioactivation of nitrates in humans.

Key Words: nitroglycerin • nitric oxide • nitrates • blood flow • vasodilation

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