Vascular tolerance to nitroglycerin in ascorbate deficiency: results are in favour of an important role of oxidative stress in nitrate tolerance

摘要

In their recent article 'Vascular tolerance to nitroglycerin (GTN) in ascorbate deficiency' Wolkart et at. demonstrated an impaired vasodilator potency of GTN in ascorbate-deficient guinea pigs.1 The authors also conclude from the lack of an effect of polyethylene-glycolated superoxide dismu-tase (PEG-SOD) and catalase (PEG-catalase), that the impairment of GTN vasodilator potency induced by ascorbate deficiency is not mediated by induction of oxidative stress (their Figure 3). Although these data are interesting, especially in the context of the previous literature suggesting a role of oxidative stress in the development of nitrate tolerance, we believe that several points deserve further discussion.Recent research emphasizes the role of mitochondria in the bioactivation of organic nitrates and in triggering the processes that mediate their clinical implications, including release of a nitric oxide (NO)-containing vasodilator, induction of ischaemic preconditioning, and tolerance.2"6 A number of studies, using antioxidants of different type and different affinity, show that the release of reactive oxygen species (ROS), which appears to be instantaneous upon exposure to GTN, is a key mediator of at least the latter two processes.7,8 Of note, administration of PEG-SOD and PEG-catalase, for structural characteristics of these molecules, would be unable to modify mitochondrial ROS production, which supports an alternate explanation to the findings of Wolkart et al., i.e. that depletion of ascorbate might have impaired the redox balance of mitochondria, causing, among other changes, (partial) oxidative inhibition of the nitrate bioconverting enzyme aldehyde dehydrogenase-2 (ALDH-2). Because PEG-SOD and PEG-catalase would not interfere with this effect of ascorbate depletion, the absence of any effects of these antioxidants would not be unexpected.