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


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.
Mackenzie
Isla S
IS
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. ism22@cam.ac.uk
Maki-Petaja
Kaisa M
KM
McEniery
Carmel M
CM
Bao
Yi Ping
YP
Wallace
Sharon M
SM
Cheriyan
Joseph
J
Monteith
Sue
S
Brown
Morris J
MJ
Wilkinson
Ian B
IB
D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D018592:Cross-Over Studies; D004221:Disulfiram / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005542:Forearm / Q000098:blood supply; D005838:Genotype; D006801:Humans; D008297:Male; D005996:Nitroglycerin / Q000008:administration & dosage / Q000378:metabolism*; D009599:Nitroprusside / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism*; D014700:Verapamil / Q000008:administration & dosage
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D014700:Verapamil; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin; D004221:Disulfiram