Original ArticleRole of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Mediated Vasodilation: Observations Concerning the Dose–Response RelationshipHe, Jerry D. BSc*; Lytvyn, Yuliya PhD*,†; Zhou, Kangbin PhD‡; Parker, John D. MD*,‡,§Author Information *Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; †Division of Nephrology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; ‡Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; and §Division of Cardiology, Department of Medicine, Sinai Health System and the Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada. Reprints: John D. Parker, MD, Division of Cardiology, Mount Sinai Hospital, 600 University Avenue, Room 1609, Toronto, Ontario M5G1X5, Canada (e-mail: [email protected]). Funded by an operating grant from the Canadian Institute of Health Research. The authors report no conflicts of interest. Journal of Cardiovascular Pharmacology: June 2019 - Volume 73 - Issue 6 - p 359-364 doi: 10.1097/FJC.0000000000000673 Buy Metrics Abstract The mechanism of the bioactivation of nitroglycerin has long been controversial, with a number of suggested enzymatic pathways. More recently, aldehyde dehydrogenase-2 (ALDH-2) has been reported as the important enzyme involved in the bioactivation of nitroglycerin at therapeutically relevant concentrations. Other previously described enzyme systems can also bioactivate nitroglycerin, but only at concentrations, which are significantly higher than achieved in clinical practice. This study investigated the vascular response to nitroglycerin given over a wide range of concentrations in subjects with and without the ALDH-2 Glu504Lys polymorphism, a common genetic variant that greatly reduces the activity of ALDH-2 (n = 10 in both groups). Forearm blood flow (FBF) responses to a brachial artery infusion of nitroglycerin were assessed using venous occlusion plethysmography. Intra-arterial infusion of nitroglycerin caused a significant increase in FBF beginning at 0.464 µg/min with increasing responses seen in both groups at all infusion rates. However, there were no differences in the FBF responses to nitroglycerin in those with and without the ALDH-2 polymorphism, suggesting that ALDH-2 is not solely responsible for the bioactivation of nitroglycerin at either low (therapeutically relevant) or high concentrations of nitroglycerin. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.