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Metabolomic profiling of cellular responses to carvedilol enantiomers in vascular smooth muscle cells.

Wang M, Bai J, Chen WN, Ching CB - PLoS ONE (2010)

Bottom Line: Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood.A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction.Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomedical Engineering, College of Engineering, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Carvedilol is a non-selective β-blocker indicated in the treatment of hypertension and heart failure. Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood. Here we report the use of GC-MS metabolomic profiling to study the effects of Carvedilol enantiomers on vascular smooth muscle cells (A7r5) and to shed new light on molecular events underlying Carvedilol treatment. The metabolic analysis revealed alternations in the levels of 8 intracellular metabolites and 5 secreted metabolites in A7r5 cells incubated separately with S- and R-Carvedilol. Principal component analysis of the metabolite data demonstrated the characteristic metabolic signatures in S- and R-Carvedilol-treated cells. A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction. Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

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Related in: MedlinePlus

The representive GC-MS spectra of L-Alanine derived from total ion chromatograms.Culture medium (black), untreated cells (red), R-Carvedilol-treated cells (green) and S-Carevdilol-treated cells (blue).
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pone-0015441-g003: The representive GC-MS spectra of L-Alanine derived from total ion chromatograms.Culture medium (black), untreated cells (red), R-Carvedilol-treated cells (green) and S-Carevdilol-treated cells (blue).

Mentions: The secreted metabolites in culture medium from A7r5 cells were analysed using GC-MS system. Analysis detected 9 secreted metabolites. A representive GC-MS total ion chromatograms is shown in Figure 3 and the up-regulated metabolite L-Alanine was observed in S-Carvedilol-treated cells. The culture medium incubated at the same conditions was set as negative control. From four independent exepriments, 4 metabolites were indentified as significantly changes between samples incubated with S-Carevdilol and control, while the changes in R-Carevdilol-treated cells is less significant (Figure 4). PCA was performed on the GC-MS spectra of four biological replicates from A7r5 cells incubated with control, S- and R-Carvedilol. The PCA scores plot shown in Figure 5a demonstrates that exposure of A7r5 cells to S- or R-Carvedilol caused distinct changes in the metabolome. Loadings plot identified L-alanine, L-leucine, L-valine and succinic acid as the major discriminators between S- and R-Carvedilol-treated cells (Figure 5b).


Metabolomic profiling of cellular responses to carvedilol enantiomers in vascular smooth muscle cells.

Wang M, Bai J, Chen WN, Ching CB - PLoS ONE (2010)

The representive GC-MS spectra of L-Alanine derived from total ion chromatograms.Culture medium (black), untreated cells (red), R-Carvedilol-treated cells (green) and S-Carevdilol-treated cells (blue).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991354&req=5

pone-0015441-g003: The representive GC-MS spectra of L-Alanine derived from total ion chromatograms.Culture medium (black), untreated cells (red), R-Carvedilol-treated cells (green) and S-Carevdilol-treated cells (blue).
Mentions: The secreted metabolites in culture medium from A7r5 cells were analysed using GC-MS system. Analysis detected 9 secreted metabolites. A representive GC-MS total ion chromatograms is shown in Figure 3 and the up-regulated metabolite L-Alanine was observed in S-Carvedilol-treated cells. The culture medium incubated at the same conditions was set as negative control. From four independent exepriments, 4 metabolites were indentified as significantly changes between samples incubated with S-Carevdilol and control, while the changes in R-Carevdilol-treated cells is less significant (Figure 4). PCA was performed on the GC-MS spectra of four biological replicates from A7r5 cells incubated with control, S- and R-Carvedilol. The PCA scores plot shown in Figure 5a demonstrates that exposure of A7r5 cells to S- or R-Carvedilol caused distinct changes in the metabolome. Loadings plot identified L-alanine, L-leucine, L-valine and succinic acid as the major discriminators between S- and R-Carvedilol-treated cells (Figure 5b).

Bottom Line: Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood.A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction.Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomedical Engineering, College of Engineering, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Carvedilol is a non-selective β-blocker indicated in the treatment of hypertension and heart failure. Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood. Here we report the use of GC-MS metabolomic profiling to study the effects of Carvedilol enantiomers on vascular smooth muscle cells (A7r5) and to shed new light on molecular events underlying Carvedilol treatment. The metabolic analysis revealed alternations in the levels of 8 intracellular metabolites and 5 secreted metabolites in A7r5 cells incubated separately with S- and R-Carvedilol. Principal component analysis of the metabolite data demonstrated the characteristic metabolic signatures in S- and R-Carvedilol-treated cells. A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction. Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

Show MeSH
Related in: MedlinePlus