Oxidative inhibition of the mitochondrial aldehyde dehydrogenase promotes nitroglycerin tolerance in human blood vessels

J Am Coll Cardiol. 2007 Dec 4;50(23):2226-32. doi: 10.1016/j.jacc.2007.08.031. Epub 2007 Nov 19.

Abstract

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.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Acetylcholine / pharmacology
  • Aged
  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase, Mitochondrial
  • Drug Administration Schedule
  • Drug Tolerance / physiology*
  • Female
  • Humans
  • Male
  • Mammary Arteries / drug effects*
  • Mammary Arteries / enzymology
  • Mammary Arteries / physiopathology
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy
  • Nitric Oxide Synthase Type III / metabolism
  • Nitroglycerin / administration & dosage
  • Nitroglycerin / pharmacology*
  • Oxidative Stress / physiology
  • Saphenous Vein / drug effects*
  • Saphenous Vein / enzymology
  • Saphenous Vein / physiopathology
  • Tissue Culture Techniques
  • Vasodilator Agents / pharmacology

Substances

  • Vasodilator Agents
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial
  • Nitroglycerin
  • Acetylcholine