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Universitätsklinikum Hamburg-Eppendorf, Medizinische Klinik III, Angiologie und Kardiologie, Hamburg, Germany (A.D., M.O., M.C., P.W., K.S., M.W., A.L.K.); Universität Konstanz, Fachbereich Biologie, Konstanz, Germany (M.B., V.U.); ALPHARMA-ISIS GmbH & Co. KG, Langenfeld, Germany (D.S.); and Universitätsklinik Mainz, Medizinische Klinik II, Kardiologie, Mainz, Germany (A.M., T.M.)
Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 µM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.
Address correspondence to: Dr. Andreas Daiber, Universitätsklinikum Eppendorf, Medizinische Klinik III - Labor für Experimentelle Kadiologie, Martinistr. 52, 20246 Hamburg, Germany. E-mail: andreas.daiber{at}bioredox.com
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