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

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. 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). Linagliptin was associated with a significant improvement in endothelium-dependent relaxation (ACh Rmax; db/db 41±1%, linagliptin 73±6%,