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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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Cumulative concentration-response curves to ACh (a), SNP (b), and basal NO release (c) in endothelium-intact mesenteric arteries.In each group (a, b), mesenteric arteries were prcontracted with PE to a similar levels: (a) normal 66±2, normal+linagliptin 64±1, diabetic 65±1, diabetic+linagliptin 66±1, (b) normal 64±1, normal+linagliptin 64±1, diabetic 61±6, diabetic+linagliptin 66±1%KPSS, n = 7–10 experiments. Results are shown as mean±SEM. **P<0.01, ***P<0.001 See Table 2 or results section for pEC50 and Rmax values derived from this data.
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pone.0143941.g003: Cumulative concentration-response curves to ACh (a), SNP (b), and basal NO release (c) in endothelium-intact mesenteric arteries.In each group (a, b), mesenteric arteries were prcontracted with PE to a similar levels: (a) normal 66±2, normal+linagliptin 64±1, diabetic 65±1, diabetic+linagliptin 66±1, (b) normal 64±1, normal+linagliptin 64±1, diabetic 61±6, diabetic+linagliptin 66±1%KPSS, n = 7–10 experiments. Results are shown as mean±SEM. **P<0.01, ***P<0.001 See Table 2 or results section for pEC50 and Rmax values derived from this data.

Mentions: Neither diabetes nor linagliptin treatment had any effect on the level of contraction to the high K+ physiological saline solution (KPSS, KCl 123 mmol/l, data not shown). The sensitivity, but not the maximum relaxation, to ACh was significantly reduced in mesenteric arteries from diabetic rats (Fig 3A, Table 2), whereas the sensitivity and the maximum relaxation to sodium nitroprusside (SNP) were not affected (Fig 3B). Four weeks of linagliptin treatment (2 mg/kg per day, oral gavage) did not affect the response to ACh in mesenteric arteries from normal rats, but in diabetic rats treated with linagliptin, the sensitivity to ACh was significantly increased in comparison to the sensitivity and response to ACh in mesenteric arteries from untreated diabetic rats (Fig 3A, Table 2). The treatment with linagliptin had no effect on the response to SNP in normal or diabetic rats (Fig 3B).


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)

Cumulative concentration-response curves to ACh (a), SNP (b), and basal NO release (c) in endothelium-intact mesenteric arteries.In each group (a, b), mesenteric arteries were prcontracted with PE to a similar levels: (a) normal 66±2, normal+linagliptin 64±1, diabetic 65±1, diabetic+linagliptin 66±1, (b) normal 64±1, normal+linagliptin 64±1, diabetic 61±6, diabetic+linagliptin 66±1%KPSS, n = 7–10 experiments. Results are shown as mean±SEM. **P<0.01, ***P<0.001 See Table 2 or results section for pEC50 and Rmax values derived from this data.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143941.g003: Cumulative concentration-response curves to ACh (a), SNP (b), and basal NO release (c) in endothelium-intact mesenteric arteries.In each group (a, b), mesenteric arteries were prcontracted with PE to a similar levels: (a) normal 66±2, normal+linagliptin 64±1, diabetic 65±1, diabetic+linagliptin 66±1, (b) normal 64±1, normal+linagliptin 64±1, diabetic 61±6, diabetic+linagliptin 66±1%KPSS, n = 7–10 experiments. Results are shown as mean±SEM. **P<0.01, ***P<0.001 See Table 2 or results section for pEC50 and Rmax values derived from this data.
Mentions: Neither diabetes nor linagliptin treatment had any effect on the level of contraction to the high K+ physiological saline solution (KPSS, KCl 123 mmol/l, data not shown). The sensitivity, but not the maximum relaxation, to ACh was significantly reduced in mesenteric arteries from diabetic rats (Fig 3A, Table 2), whereas the sensitivity and the maximum relaxation to sodium nitroprusside (SNP) were not affected (Fig 3B). Four weeks of linagliptin treatment (2 mg/kg per day, oral gavage) did not affect the response to ACh in mesenteric arteries from normal rats, but in diabetic rats treated with linagliptin, the sensitivity to ACh was significantly increased in comparison to the sensitivity and response to ACh in mesenteric arteries from untreated diabetic rats (Fig 3A, Table 2). The treatment with linagliptin had no effect on the response to SNP in normal or diabetic rats (Fig 3B).

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