Dataset Information

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.

ABSTRACT:

Background and purpose

Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator.

Experimental approach

Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) and ALDH-2-/- mice. Activity of the cGMP-dependent kinase-I (reflected by levels of phosphorylated VAsodilator Stimulated Phosphoprotein, P-VASP) was quantified by Western blot analysis, mitochondrial dehydrogenase activity by HPLC. Following incubation of isolated mitochondria with PETN, PETriN-chromophore and PEDN, metabolites were quantified using chemiluminescence nitrogen detection and mass spectrometry.

Key results

Compared to WT, vasorelaxation in response to PETN, PETriN and GTN was attenuated about 10fold in ALDH-2-/- mice, identical to WT vessels preincubated with inhibitors of ALDH-2. Reduced vasodilator potency correlated with reduced P-VASP formation and diminished biotransformation of the tetranitrate- and trinitrate-compounds. None of these findings were observed for PEDN, GDN and PEMN.

Conclusions and implications

Our results support the crucial role of ALDH-2 in bioactivating highly reactive nitrates like GTN, PETN and PETriN. ALDH-2-mediated relaxation by organic nitrates therefore depends mainly on the number of nitrate groups. Less potent nitrates like PEDN, GDN and PEMN are apparently biotransformed by other pathways.

SUBMITTER: Wenzel P

PROVIDER: S-EPMC2189719 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Publications

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.

Wenzel P P Hink U U Oelze M M Seeling A A Isse T T Bruns K K Steinhoff L L Brandt M M Kleschyov A L AL Schulz E E Lange K K Weiner H H Lehmann J J Lackner K J KJ Kawamoto T T Münzel T T Daiber A A

British journal of pharmacology 20070115 4

<h4>Background and purpose</h4>Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator.<h4>Experimental approach</h4>Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl ...[more]

PMID: 17220910

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Project description:OBJECTIVE:We have previously found that acute psychological stress may affect mitochondria and trigger an increase in serum mitochondrial DNA, known as circulating cell-free mtDNA (ccf-mtDNA). Similar to other stress reactivity measures, there are substantial unexplained inter-individual differences in the magnitude of ccf-mtDNA reactivity, as well as within-person differences across different occasions of testing. Here, we sought to identify psychological and physiological predictors of ccf-mtDNA reactivity using machine learning-based multivariate classifiers. METHOD:We used data from serum ccf-mtDNA concentration measured pre- and post-stress in 46 healthy midlife adults tested on two separate occasions. To identify variables predicting the magnitude of ccf-mtDNA reactivity, two multivariate classification models, partial least-squares discriminant analysis (PLS-DA) and random forest (RF), were trained to discriminate between high and low ccf-mtDNA responders. Potential predictors used in the models included state variables such as physiological measures and affective states, and trait variables such as sex and personality measures. Variables identified across both models were considered to be predictors of ccf-mtDNA reactivity and selected for downstream analyses. RESULTS:Identified predictors were significantly enriched for state over trait measures (X2?=?7.03; p?=?0.008) and for physiological over psychological measures (X2?=?4.36; p?=?0.04). High responders were more likely to be male (X2?=?26.95; p?<?0.001) and differed from low-responders on baseline cardiovascular and autonomic measures, and on stress-induced reduction in fatigue (Cohen's d?=?0.38-0.73). These group-level findings also accurately accounted for within-person differences in 90% of cases. CONCLUSION:These results suggest that acute cardiovascular and psychological indices, rather than stable individual traits, predict stress-induced ccf-mtDNA reactivity. This work provides a proof-of-concept that machine learning approaches can be used to explore determinants of inter-individual and within-person differences in stress psychophysiology.

Dataset Information

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.

Similar Datasets

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