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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Autores principales:	Woodman OL, Ortega JM, Hart JL, Klein T, Potocnik S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	diabetes DPP-4 inhibitor endothelium-dependent relaxation glimepiride linagliptin reactive oxygen species Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/a59d569264924aebbc71eba60415f80c
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spelling	oai:doaj.org-article:a59d569264924aebbc71eba60415f80c2021-12-02T03:08:47ZInfluence 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 glimepiride1178-7007https://doaj.org/article/a59d569264924aebbc71eba60415f80c2019-08-01T00:00:00Zhttps://www.dovepress.com/influence-of-type-4-dipeptidyl-peptidase-inhibition-on-endothelium-dep-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Owen 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 speciesWoodman OLOrtega JMHart JLKlein TPotocnik SDove Medical PressarticlediabetesDPP-4 inhibitorendothelium-dependent relaxationglimepiridelinagliptinreactive oxygen speciesSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 12, Pp 1449-1458 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	diabetes DPP-4 inhibitor endothelium-dependent relaxation glimepiride linagliptin reactive oxygen species Specialties of internal medicine RC581-951
spellingShingle	diabetes DPP-4 inhibitor endothelium-dependent relaxation glimepiride linagliptin reactive oxygen species Specialties of internal medicine RC581-951 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
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
format	article
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
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_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_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_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
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/a59d569264924aebbc71eba60415f80c
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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

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