Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance.
Recent studies suggest that mitochondrial aldehyde dehydrogenase (ALDH-2) plays a central role in the process of nitroglycerin (glyceryl trinitrate, GTN) biotransformation in vivo and that its inhibition accounts for mechanism-based tolerance in vitro. The extent to which ALDH-2 contributes to GTN tolerance (impaired relaxation to GTN) and cross-tolerance (impaired endothelium-dependent relaxation) in vivo remain to be elucidated. Rats were treated for three days with GTN. Infusions were accompanied by decreases in vascular ALDH-2 activity, GTN biotransformation, and cGMP-dependent kinase (cGK-I) activity. Further, whereas in control vessels, multiple inhibitors and substrates of ALDH-2 reduced both GTN-stimulation of cGKI and GTN-induced vasodilation, these agents had little effect on tolerant vessels. A state of functional tolerance (in the GTN/cGMP pathway) was recapitulated in cultured endothelial cells by knocking down mitochondrial DNA (rho(0) cells). In addition, GTN increased the production of reactive oxygen species (ROS) by mitochondria, and these increases were associated with impaired relaxation to acetylcholine. Finally, antioxidants/reductants decreased mitochondrial ROS production and restored ALDH-2 activity. These observations suggest that nitrate tolerance is mediated, at least in significant part, by inhibition of vascular ALDH-2 and that mitochondrial ROS contribute to this inhibition. Thus, GTN tolerance may be viewed as a metabolic syndrome characterized by mitochondrial dysfunction.
Sydow
Karsten
K
The University Hospital Eppendorf, Division of Cardiology, Hamburg, Germany.
Daiber
Andreas
A
Oelze
Matthias
M
Chen
Zhiqiang
Z
August
Michael
M
Wendt
Maria
M
Ullrich
Volker
V
Mülsch
Alexander
A
Schulz
Eberhard
E
Keaney
John F
JF
Stamler
Jonathan S
JS
Münzel
Thomas
T
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004361:Drug Tolerance; D008928:Mitochondria / Q000201:enzymology*; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014665:Vasodilator Agents / Q000378:metabolism*
D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D006152:Cyclic GMP