Cardiovascular Research Advance Access originally published online on June 25, 2008
Cardiovascular Research 2008 79(4):724; doi:10.1093/cvr/cvn175
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Vascular tolerance to nitroglycerin in ascorbate deficiency: results are in favour of an important role of oxidative stress in nitrate tolerance: reply
Department of Pharmacology and Toxicology
Karl-Franzens University Graz
Universitätsplatz 2
A-8010 Graz
Austria
Tel: +43 316 380 5567
Fax: +43 316 380 9890
E-mail address: mayer{at}uni-graz.at
In their comment to our recent study on the development of vascular tolerance to nitroglycerin (GTN) upon long-term ascorbate deprivation of guinea pigs,1 Daiber and Gori suggest that our data are in favour of an important role of oxidative stress in nitrate tolerance.2 We wish to point out that this issue was not a major focus of our study and cannot be decided in the absence of additional data, in particular measurements of vascular stress parameters. Nevertheless, unlike Daiber and Gori, we do not think that our results support the oxidative stress hypothesis of nitrate tolerance in this experimental model. As discussed in the paper, we are well aware of the limitations of the polyethylene glycol-conjugated superoxide dismutase/catalase experiments (which were requested by a reviewer of the paper), but the lack of effect of these widely applied scavenging enzymes is only one out of several observations seriously questioning the involvement of superoxide in vascular nitrate tolerance induced by ascorbate deficiency.
First, we did not observe cross-tolerance to a direct nitric oxide (NO) donor, i.e. ascorbate deprivation did not affect vascular NO availability, as would be expected if superoxide was involved. Secondly, according to the view of Daiber and Gori, oxidative stress impairs GTN bioactivation through inactivation of mitochondrial aldehyde dehydrogenase (ALDH-2), but ascorbate deficiency did not cause ALDH-2 inactivation in liver mitochondria,1 even though liver ascorbate levels were reduced by >90% after 2 weeks of ascorbate deprivation (Wenzl MV, Wölkart G, Beretta M, Stessel H, Schmidt K, Mayer B, manuscript in preparation). Thirdly, the development of vascular tolerance to GTN was markedly delayed compared with the drop in plasma ascorbate levels, suggesting that ascorbate deficiency triggers a slow adaptive process rather than having an acute oxidative stress-related effect.
Daiber and Gori correctly note that ascorbate-deficient blood vessels were 1.3- to two-fold more sensitive to ALDH inhibitors than controls (although these small differences are not statistically significant). However, even if they were real, we strongly disagree with the conclusion that this may reflect inactivation of ALDH-2 in ascorbate deficiency. Obviously, ALDH inhibitors should have had no or at least significantly less pronounced effects if ALDH-2 were already inactivated (for a detailed discussion of this issue see the study by DiFabio et al.3). However, as reasoned in our paper, the persistent sensitivity of ascorbate-deficient blood vessels to ALDH inhibitors would be consistent with downregulation of vascular ALDH-2 expression, which would also explain the delayed development of nitrate tolerance in this model. We are currently investigating this possibility in genetically modified mice that are unable to synthesize ascorbate.4
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- Wölkart G, Wenzl MV, Beretta M, Stessel H, Schmidt K, Mayer B. Vascular tolerance to nitroglycerin in ascorbate deficiency. Cardiovasc Res (2008) 79:304–312.
[Abstract/Free Full Text] - Daiber A, Gori T. Vascular tolerance to nitroglycerin in ascorbate deficiency - results are in favor of an important role of oxidative stress in nitrate tolerance. Cardiovasc Res (2008) 79:722–723.
[Free Full Text] - DiFabio J, Yanbin J, Vasiliou V, Thatcher RJ, Bennett BM. Role of mitochondrial aldehyde dehydrogenase in nitrate tolerance. Mol Pharmacol (2003) 64:1109–1116.
[Abstract/Free Full Text] - Maeda N, Hagihara H, Nakata Y, Hiller S, Wilder J, Reddick R. Aortic wall damage in mice unable to synthesize ascorbic acid. Proc Natl Acad Sci USA (2000) 97:841–846.
[Abstract/Free Full Text]
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