Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride
Owen L Woodman,1 Jacinta M Ortega,1 Joanne L Hart,1 Thomas Klein,2 Simon Potocnik11School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia; 2Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, GermanyCorrespondence: Owen L WoodmanBaker...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2019-08-01
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| Series: | Diabetes, Metabolic Syndrome and Obesity |
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| Online Access: | https://www.dovepress.com/influence-of-type-4-dipeptidyl-peptidase-inhibition-on-endothelium-dep-peer-reviewed-article-DMSO |
| _version_ | 1797935634367643648 |
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| author | Woodman OL Ortega JM Hart JL Klein T Potocnik S |
| author_facet | Woodman OL Ortega JM Hart JL Klein T Potocnik S |
| author_sort | Woodman OL |
| collection | DOAJ |
| description | Owen L Woodman,1 Jacinta M Ortega,1 Joanne L Hart,1 Thomas Klein,2 Simon Potocnik11School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia; 2Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, GermanyCorrespondence: Owen L WoodmanBaker Heart & Diabetes Institute, PO Box 6492, Melbourne 3004, AustraliaTel +61 38 532 1917Email owen.woodman@baker.edu.auPurpose: The aim of this study was to investigate the effects of the type-4 dipeptidyl peptidase (DPP-4) inhibitors linagliptin and vildagliptin as well as the sulfonylurea glimepiride on endothelium-dependent relaxation of aortae from female db/db mice with established hyperglycemia to determine whether these treatments were able to attenuate diabetes-induced endothelial dysfunction.Materials and methods: The mice were treated with glimepiride (2 mg/kg po per day, weeks 1–6, n=12), glimepiride plus vildagliptin (glimepiride 2 mg/kg po per day, weeks 1–6; vildagliptin 3 mg/kg po per day, weeks 4–6, n=11), glimepiride plus linagliptin (glimepiride 2 mg/kg po per day, weeks 1–6; linagliptin 3 mg/kg po per day, weeks 4–6, n=11) or linagliptin (3 mg/kg po per day, weeks 1–6, n=12). Endothelium-dependent relaxation using acetylcholine was assessed in the absence and presence of pharmacological tools (TRAM-34 1 μM; apamin 1 μM; N-nitro-L-arginine [L-NNA] 100 μM; 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one [ODQ] 10 μM) to distinguish relaxation mediated by nitric oxide (NO).Results: Linagliptin was associated with a significant improvement in endothelium-dependent relaxation (ACh Rmax; db/db 41±1%, linagliptin 73±6%, p<0.05). The enhanced response was maintained in the presence of TRAM-34+ apamin (ACh Rmax; db/db 23±6%, linagliptin 60±6%, p<0.01), ie, when the endothelium-dependent relaxation was mediated by NO. There was no evidence for a contribution from KCa channel opening to responses under any conditions. Glimepiride had no effect on endothelium-dependent relaxation when given alone (ACh Rmax 38±3%). The addition of linagliptin or vildagliptin to glimepiride did not significantly improve endothelium-dependent relaxation. All treatments caused some decrease in aortic superoxide production but the effect of linagliptin was significantly greater than glimepiride (linagliptin 534±60 relative luminescence unit [RLU], glimepiride 1471±265 RLU, p<0.05).Conclusion: Linagliptin is superior to glimepiride in regard to the preservation of endothelium-dependent relaxation in the presence of hyperglycemia and the improvement in endothelial function in response to linagliptin treatment is associated with greater antioxidant activity compared to glimepiride.Keywords: diabetes, DPP-4 inhibitor, endothelium-dependent relaxation, glimepiride, linagliptin, reactive oxygen species |
| first_indexed | 2024-04-10T18:17:11Z |
| format | Article |
| id | doaj.art-a59d569264924aebbc71eba60415f80c |
| institution | Directory Open Access Journal |
| issn | 1178-7007 |
| language | English |
| last_indexed | 2024-04-10T18:17:11Z |
| publishDate | 2019-08-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Diabetes, Metabolic Syndrome and Obesity |
| spelling | doaj.art-a59d569264924aebbc71eba60415f80c2023-02-02T08:32:01ZengDove Medical PressDiabetes, Metabolic Syndrome and Obesity1178-70072019-08-01Volume 121449145847908Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepirideWoodman OLOrtega JMHart JLKlein TPotocnik SOwen L Woodman,1 Jacinta M Ortega,1 Joanne L Hart,1 Thomas Klein,2 Simon Potocnik11School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia; 2Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma, Biberach, GermanyCorrespondence: Owen L WoodmanBaker Heart & Diabetes Institute, PO Box 6492, Melbourne 3004, AustraliaTel +61 38 532 1917Email owen.woodman@baker.edu.auPurpose: The aim of this study was to investigate the effects of the type-4 dipeptidyl peptidase (DPP-4) inhibitors linagliptin and vildagliptin as well as the sulfonylurea glimepiride on endothelium-dependent relaxation of aortae from female db/db mice with established hyperglycemia to determine whether these treatments were able to attenuate diabetes-induced endothelial dysfunction.Materials and methods: The mice were treated with glimepiride (2 mg/kg po per day, weeks 1–6, n=12), glimepiride plus vildagliptin (glimepiride 2 mg/kg po per day, weeks 1–6; vildagliptin 3 mg/kg po per day, weeks 4–6, n=11), glimepiride plus linagliptin (glimepiride 2 mg/kg po per day, weeks 1–6; linagliptin 3 mg/kg po per day, weeks 4–6, n=11) or linagliptin (3 mg/kg po per day, weeks 1–6, n=12). Endothelium-dependent relaxation using acetylcholine was assessed in the absence and presence of pharmacological tools (TRAM-34 1 μM; apamin 1 μM; N-nitro-L-arginine [L-NNA] 100 μM; 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one [ODQ] 10 μM) to distinguish relaxation mediated by nitric oxide (NO).Results: Linagliptin was associated with a significant improvement in endothelium-dependent relaxation (ACh Rmax; db/db 41±1%, linagliptin 73±6%, p<0.05). The enhanced response was maintained in the presence of TRAM-34+ apamin (ACh Rmax; db/db 23±6%, linagliptin 60±6%, p<0.01), ie, when the endothelium-dependent relaxation was mediated by NO. There was no evidence for a contribution from KCa channel opening to responses under any conditions. Glimepiride had no effect on endothelium-dependent relaxation when given alone (ACh Rmax 38±3%). The addition of linagliptin or vildagliptin to glimepiride did not significantly improve endothelium-dependent relaxation. All treatments caused some decrease in aortic superoxide production but the effect of linagliptin was significantly greater than glimepiride (linagliptin 534±60 relative luminescence unit [RLU], glimepiride 1471±265 RLU, p<0.05).Conclusion: Linagliptin is superior to glimepiride in regard to the preservation of endothelium-dependent relaxation in the presence of hyperglycemia and the improvement in endothelial function in response to linagliptin treatment is associated with greater antioxidant activity compared to glimepiride.Keywords: diabetes, DPP-4 inhibitor, endothelium-dependent relaxation, glimepiride, linagliptin, reactive oxygen specieshttps://www.dovepress.com/influence-of-type-4-dipeptidyl-peptidase-inhibition-on-endothelium-dep-peer-reviewed-article-DMSOdiabetesDPP-4 inhibitorendothelium-dependent relaxationglimepiridelinagliptinreactive oxygen species |
| spellingShingle | Woodman OL Ortega JM Hart JL Klein T Potocnik S Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride Diabetes, Metabolic Syndrome and Obesity diabetes DPP-4 inhibitor endothelium-dependent relaxation glimepiride linagliptin reactive oxygen species |
| title | Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride |
| title_full | Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride |
| title_fullStr | Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride |
| title_full_unstemmed | Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride |
| title_short | Influence of type-4 dipeptidyl peptidase inhibition on endothelium-dependent relaxation of aortae from a db/db mouse model of type 2 diabetes: a comparison with the effect of glimepiride |
| title_sort | influence of type 4 dipeptidyl peptidase inhibition on endothelium dependent relaxation of aortae from a db db mouse model of type 2 diabetes a comparison with the effect of glimepiride |
| topic | diabetes DPP-4 inhibitor endothelium-dependent relaxation glimepiride linagliptin reactive oxygen species |
| url | https://www.dovepress.com/influence-of-type-4-dipeptidyl-peptidase-inhibition-on-endothelium-dep-peer-reviewed-article-DMSO |
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