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Role of Mitochondrial Aldehyde Dehydrogenase in Nitrate Tolerance

Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada (J.D., Y.J., B.M.B.); Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado (V.V.); and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (G.R.J.T.)

Glyceryl trinitrate (GTN) is used in the treatment of angina pectoris and cardiac failure, but the rapid onset of GTN tolerance limits its clinical utility. Research suggests that a principal cause of tolerance is inhibition of an enzyme responsible for the production of physiologically active concentrations of NO from GTN. This enzyme has not conclusively been identified. However, the mitochondrial aldehyde dehydrogenase (ALDH2) is inhibited in GTN-tolerant tissues and produces from GTN, which is proposed to be converted to NO within mitochondria. To investigate the role of this enzyme in GTN tolerance, cumulative GTN concentration-response curves were obtained for both GTN-tolerant and -nontolerant rat aortic rings treated with the ALDH inhibitor cyanamide or the ALDH substrate propionaldehyde. Tolerance to GTN was induced using both in vivo and in vitro protocols. The in vivo protocol resulted in almost complete inhibition of ALDH2 activity and GTN biotransformation in hepatic mitochondria, indicating that long-term GTN exposure results in inactivation of the enzyme. Treatment with cyanamide or propionaldehyde caused a dose-dependent increase in the EC₅₀ value for GTN-induced relaxation of similar magnitude in both tolerant and nontolerant aorta, suggesting that although cyanamide and propionaldehyde inhibit GTN-induced vasodilation, these inhibitors do not affect the enzyme or system involved in tolerance development to GTN. Treatment with cyanamide or propionaldehyde did not significantly inhibit 1,1-diethyl-2-hydroxy-2-nitrosohydrazine-mediated vasodilation in tolerant or nontolerant aorta, indicating that these ALDH inhibitors do not affect the downstream effectors of NO-induced vasodilation. Immunoblot analysis indicated that the majority of vascular ALDH2 is present in the cytoplasm, suggesting that mitochondrial biotransformation of GTN by ALDH2 plays a minor role in the overall vascular biotransformation of GTN by this enzyme.

Address correspondence to: Dr. B. M. Bennett, Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada K7L 3N6. E-mail: bennett{at}post.queensu.ca

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