title: Aldehyde dehydrogenase-independent bioactivation of nitroglycerin in porcine and bovine blood vessels.
abstract: The vascular bioactivation of the antianginal drug nitroglycerin (GTN), yielding 1,2-glycerol dinitrate and nitric oxide or a related activator of soluble guanylate cyclase, is catalyzed by aldehyde dehydrogenase-2 (ALDH2) in rodent and human blood vessels. The essential role of ALDH2 has been confirmed in many studies and is considered as general principle of GTN-induced vasodilation in mammals. However, this view is challenged by an early report showing that diphenyleneiodonium, which we recently characterized as potent ALDH2 inhibitor, has no effect on GTN-induced relaxation of bovine coronary arteries (De La Lande et al., 1996). We investigated this issue and found that inhibition of ALDH2 attenuates GTN-induced coronary vasodilation in isolated perfused rat hearts but has no effect on relaxation to GTN of bovine and porcine coronary arteries. This observation is explained by low levels of ALDH2 protein expression in bovine coronary arteries and several types of porcine blood vessels. ALDH2 mRNA expression and the rates of GTN denitration were similarly low, excluding a significant contribution of ALDH2 to the bioactivation of GTN in these vessels. Attempts to identify the responsible pathway with enzyme inhibitors did not provide conclusive evidence for the involvement of ALDH3A1, cytochrome P450, or GSH-S-transferase. Thus, the present manuscript describes a hitherto unrecognized pathway of GTN bioactivation in bovine and porcine blood vessels. If present in the human vasculature, this pathway might contribute to the therapeutic effects of organic nitrates that are not metabolized by ALDH2.
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Neubauer
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Wölkart
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Marissa
authors.initials: M
authors.lastname: Opelt
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Schwarzenegger
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Marielies
authors.initials: M
authors.lastname: Hofinger
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Neubauer
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kollau
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria.
authors.forename: Astrid
authors.initials: A
authors.lastname: Schrammel
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Austria. Electronic address: mayer@uni-graz.at.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D005996:Nitroglycerin / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin
keywords: Aldehyde dehydrogenase-2; Denitration; Nitroglycerin; Protein expression; Vascular relaxation