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Potent inhibition of nitroglycerin bioactivation by diphenyleneiodonium (DIP)
© Neubauer et al; licensee BioMed Central Ltd. 2013
- Published: 29 August 2013
Aldehyde dehydrogenase-2 (ALDH2) catalyzes vascular bioactivation of the antianginal drug nitroglycerin (GTN) to yield nitric oxide (NO) or a related species that activates soluble guanylate cyclase (sGC), resulting in cGMP-mediated vasodilation . Accordingly, established ALDH2 inhibitors attenuate GTN-induced vasorelaxation in vitro and in vivo. However, the ALDH2 hypothesis has not been reconciled with early studies demonstrating potent inhibition of the GTN response by diphenyleneiodonium (DPI) , a widely used inhibitor of flavoproteins, in particular NADPH oxidases. We addressed this issue and investigated the effects of DPI on GTN-induced relaxation of rat aortic rings and the function of purified ALDH2.
The identification of DPI as potent ALDH2 inhibitor may have implications beyond the cardiovascular pharmacology of organic nitrates. A well established function of ALDH2 is detoxification of reactive aldehydes in liver and heart. NADPH oxidase activation has been implicated in both alcohol-induced liver injury and cardiac dysfunction. In view of the present results, showing that DPI potently inhibits the various enzymatic functions of ALDH2, it may be necessary to revise some of the earlier conclusions that are based on inhibitory effects of aryliodonium compounds.
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