Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance

Figures

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  Figure 1. Kinetic plots representing the conversion of ADMA to L-citrulline by DDAH11. Protein linearity (A) and time linearity (B) data were collected in singlicate. For ADMA concentration versus rate (C) each data point is the mean of three singlicate experiments and error bars represent the standard error. The data is represented as an Eadie-Hoffstee transform in (D). The Michaelis-Menten fit is shown as a solid line in panel C and D.

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  Figure 2. Concentration dependent inhibition of DDAH1 by ZST316 (positive control), esomeprazole (EPZ), lansoprazole (LPZ), omeprazole (OPZ), pantoprazole (PPZ) and rabeprazole (RPZ). Residual DDAH1 activity is reported as percentage of control activity. Each data point represents the mean of at least two single experiments. Error bars represent the standard deviation. *P < 0.01 for trend; #P < 0.05 vs. baseline; ^P < 0.01 vs. baseline.

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  Figure 3. Reversibility of PPI binding to DDAH1. Measurement of DDAH1 activity is expressed as percentage of control activity (incubation with no PPI). Each data point represents the mean of two sets of triplicate experiments (10-fold PPI dilution) or one triplicate experiment (no PPI dilution). Error bars indicate the standard deviation. *P < 0.05; **P < 0.01.

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  Figure 4. Detection of rabeprazole (RPZ) degradation products. UV chromatograms detected at 280 nm for pantoprazole (PPZ) and RPZ at time 0 (A and B, respectively), after 30 min of incubation (C and D, respectively) and after 4 h of incubation (E and F, respectively). Additional peaks in RPZ chromatograms are attributed to RPZ degradation products and were identified using published mass spectral data17 (data not shown). The arrow indicates the residual peak for RPZ.