Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance

Abstract

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 (ρ 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.

In vitro and in vivo Characterization of a New Organic Nitrate Hybrid Drug Covalently Bound to Pioglitazone

“…Nitroglycerin at 10 or 100 µmol/l also had little effect on RONS formation regardless of incubation time; however, at 1,000 µmol/l, GTN increased RONS formation approximately 4-fold over control levels after 5 min of incubation. This rapid induction of RONS by GTN at high concentrations is well established [31,32]. Interestingly, unlike the other compounds, the rate of RONS formation induced by GTN did not change after a 20-min incubation.…”

“…Mitochondrial oxidative stress has been identified as a hallmark of GTN-induced nitrate tolerance [31,32]. Therefore, the induction of RONS was assessed in cardiac mitochondria isolated from the in vivo treated rats (fig.…”

Endothelial dysfunction: a strategic target in the treatment of hypertension?

“…However, continuous administration comprises a clinical problem due to the desensitization of the target enzyme guanylyl cyclase, leading to crosstolerance to other endothelium-dependent vasodilators [73]. Other concerns involve the ability of nitroglycerin to increase ROS indirectly [74].…”

Nitroglycerin induces DNA damage and vascular cell death in the setting of nitrate tolerance

“…Under chronic therapy, the efficacy of organic nitrate therapy is seriously impaired by the development of pseudotolerance, due to an increase in catecholamines and activation of the renin-angiotensinaldosterone system, true vascular tolerance and endothelial dysfunction accompanied by increased oxidative stress [31,38,39]. Our previous studies identified oxidative stress as a hallmark of nitrate tolerance and nitrate-associated endothelial dysfunction [42,47,58]. Sources of nitrateinduced reactive oxygen and nitrogen species formation are the mitochondrial respiratory chain complexes [8,13], activation of the phagocytic NADPH oxidase [42,60] and uncoupling of the endothelial nitric oxide synthase (eNOS) [31,40].…”