Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Abstract

Recent animal data suggest that reduced lipoic acid (LA) prevents oxidative inhibition of the nitrate bioactivating enzyme, the mitochondrial aldehyde dehydrogenase (ALDH-2), and that pentaerythritol tetranitrate (PETN) does not induce nitrate tolerance because of its intrinsic antioxidative properties, thereby preserving ALDH-2 activity. We sought to determine whether ALDH-2 activity in circulating white blood cells (WBCs) can be used to monitor nitrate tolerance and whether LA can prevent nitroglycerin tachyphylaxis in humans. Eight healthy male volunteers received, in randomized order, a single dose of glyceryl trinitrate (GTN; 0.8 mg), PETN (80 mg), or GTN plus LA (600 mg) orally. GTN (30 min) and PETN (120 min) administration lead to a comparable dilation of the brachial artery (15 +/- 1%). In contrast to PETN, acute GTN treatment resulted in a 60% decrease in WBC ALDH-2 activity (high-performance liquid chromatography), 30% reduction of nitrate bioactivation, and 25% decrease in serum antioxidant capacity (fluorescence assay), which all were prevented by pretreatment with LA. Mechanistic studies in rats identified oxidative stress, ALDH-2 inactivation, and vascular dysfunction as common features in acute and chronic nitrate tolerance. Treatment with GTN, but not PETN, acutely inhibits ALDH-2 activity and nitrate bioactivation in healthy volunteers. These effects were prevented by LA pretreatment, emphasizing the role of oxidative stress-triggered ALDH-2 dysfunction. Assessment of WBC ALDH-2 activity could be used as an easily accessible marker for the detection of nitroglycerin-induced tachyphylaxis in humans and may be of high clinical interest because recent data suggest that ALDH-2 activity correlates with protection from ischemic heart damage in infarct models.