title: Bioactivation of pentaerythrityl tetranitrate by mitochondrial aldehyde dehydrogenase.
abstract: Mitochondrial aldehyde dehydrogenase (ALDH2) contributes to vascular bioactivation of the antianginal drugs nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN), resulting in cGMP-mediated vasodilation. Although continuous treatment with GTN results in the loss of efficacy that is presumably caused by inactivation of ALDH2, PETN does not induce vascular tolerance. To clarify the mechanisms underlying the distinct pharmacological profiles of GTN and PETN, bioactivation of the nitrates was studied with aortas isolated from ALDH2-deficient and nitrate-tolerant mice, isolated mitochondria, and purified ALDH2. Pharmacological inhibition or gene deletion of ALDH2 attenuated vasodilation to both GTN and PETN to virtually the same degree as long-term treatment with GTN, whereas treatment with PETN did not cause tolerance. Purified ALDH2 catalyzed bioactivation of PETN, assayed as activation of soluble guanylate cyclase (sGC) and formation of nitric oxide (NO). The EC(50) value of PETN for sGC activation was 2.2 ± 0.5 μM. Denitration of PETN to pentaerythrityl trinitrate was catalyzed by ALDH2 with a specific activity of 9.6 ± 0.8 nmol · min(-1) · mg(-1) and a very low apparent affinity of 94.7 ± 7.4 μM. In contrast to GTN, PETN did not cause significant inactivation of ALDH2. Our data suggest that ALDH2 catalyzes bioconversion of PETN in two distinct reactions. Besides the major denitration pathway, which occurs only at high PETN concentrations, a minor high-affinity pathway may reflect vascular bioactivation of the nitrate yielding NO. The very low rate of ALDH2 inactivation, presumably as a result of low affinity of the denitration pathway, may at least partially explain why PETN does not induce vascular tolerance.
authors.affiliation: Department of Pharmacology and Toxicology, Karl-Franzens-Universität Graz, Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Griesberger
authors.forename: Alexander
authors.initials: A
authors.lastname: Kollau
authors.forename: Gerald
authors.initials: G
authors.lastname: Wölkart
authors.forename: M Verena
authors.initials: MV
authors.lastname: Wenzl
authors.forename: Matteo
authors.initials: M
authors.lastname: Beretta
authors.forename: Michael
authors.initials: M
authors.lastname: Russwurm
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.forename: Kurt
authors.initials: K
authors.lastname: Schmidt
authors.forename: Antonius C F
authors.initials: AC
authors.lastname: Gorren
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology; D010417:Pentaerythritol Tetranitrate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
chemical_list: D024101:Mitochondrial Proteins; D010417:Pentaerythritol Tetranitrate; D009569:Nitric Oxide; C100210:pentrinitrol; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D006162:Guanylate Cyclase; D005996:Nitroglycerin