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1.
Biochem Pharmacol ; 93(4): 440-8, 2015 Feb 15.
Article in English | MEDLINE | ID: mdl-25576686

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.


Subject(s)
Aldehyde Dehydrogenase/biosynthesis , Nitroglycerin/metabolism , Vasoconstriction/physiology , Vasodilation/physiology , Aldehyde Dehydrogenase/antagonists & inhibitors , Aldehyde Dehydrogenase, Mitochondrial , Animals , Cattle , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Female , Humans , Male , Organ Culture Techniques , Rats , Rats, Sprague-Dawley , Species Specificity , Swine , Vasoconstriction/drug effects , Vasodilation/drug effects
2.
Mol Pharmacol ; 84(3): 407-14, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23793290

ABSTRACT

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. DPI (0.3 µM) inhibited the high affinity component of aortic relaxation to GTN without affecting the response to NO, indicating that the drug interfered with GTN bioactivation. Denitration and bioactivation of 1-2 µM GTN, assayed as 1,2-glycerol dinitrate formation and activation of purified sGC, respectively, were inhibited by DPI with a half-maximally active concentration of about 0.2 µM in a GTN-competitive manner. Molecular modeling indicated that DPI binds to the catalytic site of ALDH2, and this was confirmed by experiments showing substrate-competitive inhibition of the dehydrogenase and esterase activities of the enzyme. Our data identify ALDH2 as highly sensitive target of DPI and explain inhibition of GTN-induced relaxation by this drug observed previously. In addition, the data provide new evidence for the essential role of ALDH2 in GTN bioactivation and may have implications to other fields of ALDH2 research, such as hepatic ethanol metabolism and cardiac ischemia/reperfusion injury.


Subject(s)
Aldehyde Dehydrogenase/antagonists & inhibitors , Mitochondrial Proteins/antagonists & inhibitors , Nitroglycerin/metabolism , Onium Compounds/pharmacology , Vasodilator Agents/metabolism , Aldehyde Dehydrogenase/chemistry , Aldehyde Dehydrogenase, Mitochondrial , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Catalytic Domain , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Female , Humans , In Vitro Techniques , Male , Molecular Docking Simulation , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Protein Binding , Rats , Rats, Sprague-Dawley , Swine , Vasodilation/drug effects
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