Abstract 211: The DPP-4 Inhibitor Linagliptan Reverses Endothelial Dysfunction of Mesenteric Arteries From Rats Fed a Western Diet

Abstract

A high-fat ‘western’ diet (WD), a risk factor for the development of type 2 diabetes, may cause endothelial dysfunction one of the earliest events in atherogenesis. The dipeptidyl peptidase-4 (DPP-4) inhibitors are used to lower hyperglycemia in type 2 diabetes which is also associated with endothelial dysfunction. We tested whether consumption of a WD affected endothelium-dependent relaxation (EDR) of rat mesenteric arteries (MA) and whether the DPP-4 inhibitor linagliptin (1μM) improves EDR. Wistar Hooded rats were fed a standard diet (SD, 7% total fat) or WD (21% total fat) for 10 weeks. Consumption of the WD significantly increased superoxide release from MA assayed by lucigenin chemiluminescence (WD 1210±180 counts/mg versus SD 543±156 counts/mg, n=7-8, p<0.05) and linagliptin significantly reduced the vascular superoxide release (WD+linagliptin 432±102 counts/mg, p<0.05). Acetylcholine (ACh)-induced endothelium-dependent relaxation of MA was assessed using wire myography. WD significantly reduced the sensitivity to ACh (pEC50, SD 7.72±0.08, WD, 7.32±0.05 n=8, p<0.05) and treatment with linagliptin improved endothelial function (ACh pEC50 WD+linagliptin, 7.74±0.12, n=8, p<0.05). The contribution of EDHF to ACh-induced relaxation was determined in the presence of L-NNA and ODQ to block NOS and guanylate cyclase. EDHF-mediated relaxation was improved by linagliptin (pEC50, WD 6.24±0.06, WD+linagliptin 6.95±0.12, n=4-5, p<0.05). Linagliptin also significantly improved the contribution of NO (determined in the presence of TRAM-34 + apamin to block IKCa and SKCa) to relaxation (pEC50, WD 6.50±0.13, WD+linagliptin 7.30±0.10 n=4-6, p<0.05). Linagliptin significantly reduced vascular superoxide levels and improved the contribution of both NO and EDHF to preserve endothelium-dependent relaxation in rats fed a high fat diet. DPP-4 inhibition may have effects in addition to the lowering of plasma glucose to improve vascular function in diabetes.