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.
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Figure 1 Effects of In Vivo Nitroglycerin Treatment and In Vitro ALDH Inhibition on Nitroglycerin Reactivity in Human Bypass Vessels
Effects of in vivo nitroglycerin (GTN) treatment and of in vitro inhibition of the vascular aldehyde dehydrogenase (ALDH) with benomyl on GTN dose–response relationship of A. mammaria (left panel) and V. saphena (right panel). In vivo GTN treatment causes a marked shift of the GTN dose–response relationship to the right compatible with tolerance. The shift was almost identical as compared with that obtained with the ALDH inhibitor benomyl, compatible with an inhibition of the enzyme in response to chronic GTN treatment. Data are mean ± SEM from 5 to 9 patients representing 9 to 13 vessel segments/group (see Table 2). *p < 0.05 of GTN or benomyl treatment versus without pretreatment. CTR = control group.
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Figure 2 Effects of In Vivo and In Vitro Nitroglycerin Treatment on Vascular ALDH Activity in Human Bypass Vessels
In vivo nitroglycerin (GTN) treatment, in vitro GTN, as well as the use of benomyl markedly inhibited aldehyde dehydrogenase (ALDH) activity in both A. mammaria (left panel) and V. saphena (right panel). n = number of patients/vessel segments/group as shown. *p < 0.05 versus without GTN pretreatment (CTR);  p < 0.05 between vessel types.
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Figure 3 Effects of the Antioxidant Dithiothreitol on ALDH Activity in V. Saphena
Incubation of V. saphena with nitroglycerin (GTN) markedly inhibited aldehyde dehydrogenase (ALDH) activity, all of which was prevented by co-incubation with dithiothreitol (DTT); data are mean ± SEM from 6 to 7 experiments. *p < 0.05 versus without treatment (CTR).
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Figure 4 Effects of Nitroglycerin Treatment on eNOS Expression in Human Bypass Vessels
Nitroglycerin (GTN) treatment led to a significant decrease in endothelial nitric oxide synthase (eNOS) expression in A. mammaria, whereas eNOS expression in V. saphena was not affected. Data are mean ± SEM from n = 9 to 11 experiments/group. *p < 0.05 versus without GTN treatment (CTR).
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Figure 5 Effects of Nitroglycerin Treatment on ALDH-2 Expression
Nitroglycerin (GTN) treatment led to a significant decrease in mitochondrial aldehyde dehydrogenase (ALDH-2) expression in A. mammaria compared with control subjects. Data are mean ± SEM from n = 10 to 12 experiments/group. *p < 0.05 versus without GTN treatment (CTR).
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