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Inhibition of aldehyde dehydrogenase type 2 attenuates vasodilatory action of nitroglycerin in human veins

Martin W. Huellner^*, Sonja Schrepfer, Michael Weyand, Henry Weiner^¶, Isabella Wimplinger, Thomas Eschenhagen^* and Thomas Rau^*,1

^* Institute of Experimental and Clinical Pharmacology,

Department of Cardiovascular Surgery, and

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Germany;

Department of Cardiovascular Surgery, Friedrich-Alexander University, Erlangen-Nürnberg, Germany; and

^¶ Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA

¹Correspondence: Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, Hamburg 20246, Germany. E-mail: t.rau{at}uke.uni-hamburg.de

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 -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 (P0.01). 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.—Huellner, M. W., Schrepfer, S., Weyand, M., Weiner, H., Wimplinger, I., Eschenhagen, T., Rau, T. Inhibition of aldehyde dehydrogenase type 2 attenuates vasodilatory action of nitroglycerin in human veins.

Key Words: nitric oxide • organic nitrates • pharmacodynamics • biotransformation • capacitance vessels

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