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The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose.

Salheen SM, Panchapakesan U, Pollock CA, Woodman OL - PLoS ONE (2015)

Bottom Line: Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels.Linagliptin improved endothelial function indicated by a significant increase in responses to ACh.These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

ABSTRACT
The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1 μM TRAM-34, 1 μM apamin, 100 nM Ibtx, 100 μM L-NNA, 10 μM ODQ) were used to distinguish between NO and EDH-mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

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Relative contribution of NO and EDH to endothelium-dependent relaxation.NO and EDH-mediated relaxation in isolated mesenteric arteries from normal (a), diabetic (b), normal+linagliptin (c), diabetic+linagliptin (d) rats. In each group of experiments, arteries were precontracted with PE to similar levels: 63±2 (a), 65±0.6 (b), 65±1 (c), 63±1 (d) %KPSS, n = 8–9 experiments. Results are shown as mean±SEM. See Table 2 for pEC50 and Rmax values derived from this data. *P<0.05 vs normal.
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pone.0143941.g004: Relative contribution of NO and EDH to endothelium-dependent relaxation.NO and EDH-mediated relaxation in isolated mesenteric arteries from normal (a), diabetic (b), normal+linagliptin (c), diabetic+linagliptin (d) rats. In each group of experiments, arteries were precontracted with PE to similar levels: 63±2 (a), 65±0.6 (b), 65±1 (c), 63±1 (d) %KPSS, n = 8–9 experiments. Results are shown as mean±SEM. See Table 2 for pEC50 and Rmax values derived from this data. *P<0.05 vs normal.

Mentions: In mesenteric arteries from normal rats, the ACh-induced relaxation was partially reduced by either the combination of N-nitro-L-arginine (L-NNA), a NO synthase inhibitor and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor or inhibitors of intermediate-conductance calcium-activated K+ channel (IKCa), small-conductance calcium-activated K+ channel (SKCa) with 1-[(2 chlorophenyl)(diphenyl)methyl]1H pyrazole (TRAM-34), apamin and iberiotoxin (Ibtx) respectively, confirming that both NO and EDH were involved in endothelium-dependent relaxation (Fig 4A and 4B, Table 2). Further, the response to ACh-induced relaxation in mesenteric arteries from diabetic rats was significantly further reduced in the presence of either NO inhibitors or EDH inhibitors in comparison to normal rats (Table 2), indicating that the contribution of both NO and EDH to endothelium-dependent relaxation were impaired by diabetes.


The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose.

Salheen SM, Panchapakesan U, Pollock CA, Woodman OL - PLoS ONE (2015)

Relative contribution of NO and EDH to endothelium-dependent relaxation.NO and EDH-mediated relaxation in isolated mesenteric arteries from normal (a), diabetic (b), normal+linagliptin (c), diabetic+linagliptin (d) rats. In each group of experiments, arteries were precontracted with PE to similar levels: 63±2 (a), 65±0.6 (b), 65±1 (c), 63±1 (d) %KPSS, n = 8–9 experiments. Results are shown as mean±SEM. See Table 2 for pEC50 and Rmax values derived from this data. *P<0.05 vs normal.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664283&req=5

pone.0143941.g004: Relative contribution of NO and EDH to endothelium-dependent relaxation.NO and EDH-mediated relaxation in isolated mesenteric arteries from normal (a), diabetic (b), normal+linagliptin (c), diabetic+linagliptin (d) rats. In each group of experiments, arteries were precontracted with PE to similar levels: 63±2 (a), 65±0.6 (b), 65±1 (c), 63±1 (d) %KPSS, n = 8–9 experiments. Results are shown as mean±SEM. See Table 2 for pEC50 and Rmax values derived from this data. *P<0.05 vs normal.
Mentions: In mesenteric arteries from normal rats, the ACh-induced relaxation was partially reduced by either the combination of N-nitro-L-arginine (L-NNA), a NO synthase inhibitor and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor or inhibitors of intermediate-conductance calcium-activated K+ channel (IKCa), small-conductance calcium-activated K+ channel (SKCa) with 1-[(2 chlorophenyl)(diphenyl)methyl]1H pyrazole (TRAM-34), apamin and iberiotoxin (Ibtx) respectively, confirming that both NO and EDH were involved in endothelium-dependent relaxation (Fig 4A and 4B, Table 2). Further, the response to ACh-induced relaxation in mesenteric arteries from diabetic rats was significantly further reduced in the presence of either NO inhibitors or EDH inhibitors in comparison to normal rats (Table 2), indicating that the contribution of both NO and EDH to endothelium-dependent relaxation were impaired by diabetes.

Bottom Line: Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels.Linagliptin improved endothelial function indicated by a significant increase in responses to ACh.These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

View Article: PubMed Central - PubMed

Affiliation: School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.

ABSTRACT
The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1 μM TRAM-34, 1 μM apamin, 100 nM Ibtx, 100 μM L-NNA, 10 μM ODQ) were used to distinguish between NO and EDH-mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

Show MeSH
Related in: MedlinePlus