Metformin Improves Endothelial Function and Reduces Blood Pressure in Diabetic Spontaneously Hypertensive Rats Independent from Glycemia Control: Comparison to Vildagliptin

Figures

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  Figure 1. Effects of vildagliptin and metformin on SHR characteristics. Eight week old spontaneously hypertensive rats (SHR) rats were injected at t = 0 with streptozotocin (STZ, 60 mg/kg) or saline (non-STZ) to induce type-1 diabetes mellitus or not before they were treated for 12 weeks either with vildagliptin (10 mg/kg/day; open triangles) or metformin (300 mg/kg/day; open squares), or remained untreated (closed circles). Shown are the over time effects on (A) blood glucose, (B) body weight, (C) food intake, (D) urine production and (E) water intake. Data are mean ± SEM (n = 6–8 for each group). *Indicates p < 0.05 vs. untreated (STZ-)SHR at a specific time point; #indicates p < 0.05 vs. untreated (STZ-)SHR for the whole curve.

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  Figure 2. Effects of vildagliptin and metformin on endothelium-dependent relaxation in SHR aorta. Eight week old spontaneously hypertensive rats (SHR) rats were injected at t = 0 with streptozotocin (STZ-SHR, 60 mg/kg) or saline (SHR) to induce type-1 diabetes mellitus or not before they were treated for 12 weeks either with vildagliptin (10 mg/kg/day; open triangles) or metformin (300 mg/kg/day; open squares), or remained untreated (control; closed circles). Shown are the concentration-response curves of acetylcholine (ACh-)induced relaxation in isolated aorta preparations obtained at the end of the study period for A) SHR and B) STZ-SHR rats. Data are mean ± SEM (n = 6–8 for each group). *Indicates p < 0.05 vs. control for the whole curve (repeated measures ANOVA).

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  Figure 3. Effect of vildagliptin and metformin on endothelial mediators in SHR aorta. Acetylcholine-induced relaxation was studied in the absence or presence of indomethacin and/or LNMMA after which the area under the curve (AUC) was determined and used to calculate the contribution of prostaglandins (PGs, sensitive to COX-inhibition), nitric oxide (NO, sensitive to eNOS-inhibition) and EDHF (resistant to COX- plus eNOS-inhibition) to total relaxation (see also methods). Panel A and B shows the results for SHR and STZ-SHR, respectively. Data are mean ± SEM (n = 6–8 for each group). *Indicates p < 0.05 vs. control.

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  Figure 4. Linear regression analysis of endothelial mediators of aorta EDR with SBP. Shown are scatterplots for the contribution of, respectively, (A) prostaglandins (PGs), (B) nitric oxide (NO) and (C) EDHF with systolic blood pressure (SBP). Results of linear regression analysis are as indicated, with EDHF being the only mediator significantly correlated with SBP.

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  Figure 5. Plasma sulphide levels and its correlation with EDHF and SBP. Shown are (A) the average plasma sulphide levels (as a proxy of H2S) in treated and untreated SHR and STZ-SHR, and scatterplots of individual plasma sulphide levels with (B) EDHF contribution in aorta endothelium dependent relaxation and with (C) systolic blood pressure. Results of linear regression analysis are as indicated.