title: Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases.
abstract: Nitrate-based vasodilators (NBVs) are commonly used to treat multiple sequelae of atherosclerosis. A commonly used NBV, glyceryl trinitrate (GTN) is bioactivated by mitochondrial, class 2 aldehyde dehydrogenase (ALDH2). ALDH2 and other ALDHs are NAD(P)+-dependent enzymes critical to the detoxification of cytotoxic lipid-aldehydes elevated in atherosclerotic lesions, such as trans-4-hydroxy-2-nonenal (HNE). The GTN bioactivation step, however, inac-tivates ALDH2 and may alter the metabolism of these aldehydes. In this study, we tested the hypothesis that multiple ALDH enzymes are inhibited by different NBVs. ALDH2, ALDH3A, and ALDH5A were present in aorta with ALDH2 and ALDH3A localized to the smooth muscle layers. GTN (1 microM) inhibited ALDH2 activity (55 +/- 6% of control) and ablated ALDH3 activity. In contrast, isosorbide-2,5-dinitrate (ISDN, 1 microM) inhibited ALDH3 activity (1.1 +/- 0.4% of control) but did not inhibit ALDH2 activity even up to 50 microM ISDN. In homogenates of rat aorta, GTN (1 microM) inhibited the NAD+-dependent (41 +/- 5% of control) and NADP+-dependent (25 +/- 6% of control) detoxification of HNE. The inhibition of ALDH3A, but not ALDH2, could be prevented by the addition of dithiothreitol. These studies demonstrate that GTN and ISDN possess selectivity for ALDH inactivation with different mechanisms of inactivation.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND 58203, USA.
authors.forename: Tonya C
authors.initials: TC
authors.lastname: Murphy
authors.forename: Roberta
authors.initials: R
authors.lastname: Arntzen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Picklo
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000447:Aldehydes / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology; D009566:Nitrates / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D007527:Isoenzymes; D009566:Nitrates; D014665:Vasodilator Agents; D009599:Nitroprusside; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; C027576:4-hydroxy-2-nonenal