title: Inhibition of aldehyde dehydrogenase type 2 attenuates vasodilatory action of nitroglycerin in human veins.
abstract: Recent studies suggest that the mitochondrial aldehyde dehydrogenase (ALDH)2 is involved in vascular bioactivation of nitroglycerin (GTN). However, neither expression of ALDH2 nor its functional role in GTN bioactivation has been reported for the main drug target in humans, namely capacitance vessels. We investigated whether ALDH2 is expressed in human veins and whether inhibition of the enzyme attenuates nitroglycerin effects in these vessels. We determined expression of ALDH2 and dehydrogenase activity in human veins by reverse transcriptase-polymerase chain reaction, Western blotting, and immunofluorescence microscopy. In vitro contraction experiments were performed in the presence or absence of the ALDH inhibitors chloral hydrate, cyanamide, and ethoxycyclopropanol. Concentration response curves were determined for the alpha-agonist phenylephrine, nitroglycerin, and the direct NO donor diethylamine NONOate (DEA-NONOate). ALDH2 expression was largely confined to smooth muscle cells as determined by confocal immunofluorescence microscopy. Contractile responses to phenylephrine were unaffected by all ALDH inhibitors tested. In clear contrast, the ALDH inhibitors significantly reduced the potency of nitroglycerin by approximately 1 order of magnitude (P < or = 0.01). Neither of the inhibitors affected the potency of the direct NO donor DEA-NONOate, which ruled out nonspecific effects on the NO signaling cascade. In human capacitance vessels, ALDH2 is a key enzyme in the biotransformation of the frequently used antianginal drug nitroglycerin.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Huellner
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
authors.forename: Michael
authors.initials: M
authors.lastname: Weyand
authors.forename: Henry
authors.initials: H
authors.lastname: Weiner
authors.forename: Isabella
authors.initials: I
authors.lastname: Wimplinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Thomas
authors.initials: T
authors.lastname: Rau
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D002697:Chloral Hydrate / Q000494:pharmacology; D003484:Cyanamide / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D005996:Nitroglycerin / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology; D014680:Veins / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology
chemical_list: D014665:Vasodilator Agents; D002697:Chloral Hydrate; D003484:Cyanamide; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin