Oxidative inhibition of the mitochondrial aldehyde dehydrogenase promotes nitroglycerin tolerance in human blood vessels.
OBJECTIVE
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.
II Medizinische Klinik für Kardiologie und Angiologie, Johannes Gutenberg University, Mainz, Germany.
Ulrich
U
Hink
Andreas
A
Daiber
Nalan
N
Kayhan
Jordis
J
Trischler
Catharina
C
Kraatz
Matthias
M
Oelze
Hanke
H
Mollnau
Philip
P
Wenzel
Christian F
CF
Vahl
Kwok Ki
KK
Ho
Henry
H
Weiner
Thomas
T
Munzel
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D009203:Myocardial Infarction / Q000201:enzymology* / Q000503:physiopathology / Q000628:therapy; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology; D012501:Saphenous Vein / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D046509:Tissue Culture Techniques; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D005996:Nitroglycerin; D000109:Acetylcholine