Abstract 1177: The Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Plays a Key Role in the Bioactivation of Nitroglycerin and Associated Tolerance Phenomena in Human Bypass Vessels
The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted by the development of nitrate tolerance, a phenomenon that is associated with increased oxidative stress. Recent studies suggest that mitochondrial aldehyde dehydrogenase (ALDH-2) plays a central role in GTN biotransformation. Its inhibition accounts for mechanism-based tolerance in animal models. The extent to which ALDH-2 contributes to GTN tolerance (impaired relaxation to GTN) and cross-tolerance (impaired endothelium-dependent relaxation to acetylcholine) in humans remains to be elucidated.
METHODS AND RESULTS: Segments of surgically removed mammarian artery and saphenous vein not required for the bypass procedure were used to examine the vascular responsiveness to GTN and acetylcholine. The ALDH-2 activity in these segments was assessed by the conversion of a benzaldehyde derivative (100 μM) to the benzoic acid metabolite which was measured by HPLC analysis. In contrast to patients not treated with nitrates, patients who were on continuous GTN infusion for at least 48 hours before surgery showed a significant degree of tolerance to GTN in both arterial (max. relaxation 98,8 ± 1,2 vs 98,2 ± 0,8 %; EC50 7,9 vs 8,2 logM) and venous vessels studied (99,0 ± 0,4 vs 99,7 ± 0,3 %; EC50 7,6 vs 8,1 logM) and significant cross-tolerance to acetylcholine (artery: 74 ± 2 vs 84 ± 3 % and EC50 7,3 vs 7,7 logM; vein: 59 ± 3 vs 66 ± 4 % and EC50 7,2 vs 7,4 logM). Furthermore, pre-treatment with i.v. GTN lead to a marked loss in vascular ALDH activity compared to non-tolerant vessels (1,5 ± 0,2 vs 2,3 ± 0,2 μM/mg). Similarly, after incubation of control venous vessels with GTN (100 μM for 30 min) a significant decrease of ALDH activity was observed. Incubation with the ALDH-2 inhibitor benomyl (1μM) inhibited ALDH activity by 80% and shifted the dose response curves to GTN about one log to the right.
CONCLUSIONS: We conclude that long-term GTN treatment induces nitrate tolerance and endothelial dysfunction which is associated with inhibition of vascular ALDH-2 in human vessels. These findings support previous mechanistic data from in vitro and animal studies and indicate pathophysiological relevance in humans. Thus, GTN tolerance may be seen as a condition characterized by mitochondrial dysfunction.