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CLINICAL RESEARCH: CARDIAC PHARMACOLOGY

Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels

Ulrich Hink, MD^_*, Andreas Daiber, PhD^_*, Nalan Kayhan, MD, Jordis Trischler, MS^_*, Catharina Kraatz, MS^_*, Matthias Oelze, PhD^_*, Hanke Mollnau, MD^_*, Philip Wenzel, MD^_*, Christian F. Vahl, MD, Kwok Ki Ho, PhD, Henry Weiner, PhD and Thomas Munzel, MD^_*,_*

^_* II Medizinische Klinik für Kardiologie und Angiologie, Johannes Gutenberg University, Mainz, Germany
Klinik für Herz, Thorax und Gefäßchirurgie, Johannes Gutenberg University, Mainz, Germany
Purdue University, West Lafayette, Indiana. The authors have received continuous funding by the German Research Community (DFG), SFB 553 – C17 to Drs. Daiber and Munzel and MAIFOR grants from the Hospital of the Johannes Gutenberg University to Drs. Daiber, Oelze, Hink, and Wenzel

Manuscript received October 13, 2006; revised manuscript received July 10, 2007, accepted August 16, 2007.

^_* Reprint requests and correspondence: Dr. Thomas Münzel, II Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. (Email: tmuenzel{at}uni-mainz.de).

Objectives: We tested the hypothesis of whether an inhibition of the nitroglycerin (GTN) bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) contributes to GTN tolerance in human blood vessels.

Background: The hemodynamic effects of GTN are rapidly blunted by the development of tolerance, a phenomenon associated with increased formation of reactive oxygen species (ROS). Recent studies suggest that ROS-induced inhibition of ALDH-2 accounts for tolerance in animal models.

Methods: Segments of surgically removed arteria mammaria and vena saphena from patients undergoing coronary bypass surgery were used to examine the vascular responsiveness to GTN and the endothelium-dependent vasodilator acetylcholine. The ALDH-2 activity and expression in these segments were assessed by the conversion of a benzaldehyde or its derivative to the benzoic acid metabolite and by Western blotting technique.

Results: In contrast to patients not treated with nitrates (n = 36), patients treated with GTN for 48 h (n = 14) before surgery showed tolerance to GTN and endothelial dysfunction in arterial and venous vessels. In vivo GTN tolerance was mimicked in vitro by incubation of nontolerant vessels with the ALDH-2 inhibitor benomyl. In vivo GTN treatment decreased vascular aldehyde dehydrogenase activity compared with nontolerant vessels and decreased the expression of ALDH-2 in arterial tissue. Incubation of control venous vessels with GTN caused a significant attenuation of aldehyde dehydrogenase activity that was reversed by presence of the sulfhydryl group donor dithiothreitol.

Conclusions: Long-term GTN treatment induces tolerance and endothelial dysfunction in human vessels, associated with an inhibition and down-regulation of vascular ALDH-2. Thus, these findings extend results of previous animal studies to humans.

Abbreviations and Acronyms   ALDH-2 = mitochondrial aldehyde dehydrogenase   DTT = dithiothreitol   EC50 = half-maximal concentration   eNOS = endothelial nitric oxide synthase   GTN = glycerol trinitrate, nitroglycerin   ROS = reactive oxygen species

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