title: The DPP-4 inhibitor linagliptin and the GLP-1 receptor agonist exendin-4 improve endothelium-dependent relaxation of rat mesenteric arteries in the presence of high glucose.
abstract: The aim of the study was to investigate the effects of the DPP-4 inhibitors and GLP-1R agonist, exendin-4 on the mechanism(s) of endothelium-dependent relaxation in rat mesenteric arteries exposed to high glucose concentration (40 mM). Organ bath techniques were employed to investigate vascular endothelial function in rat mesenteric arteries in the presence of normal (11 mM) or high (40 mM) glucose concentrations. Pharmacological tools (1μM TRAM-34, 1μM apamin, 100 nM Ibtx, 100 μM l-NNA, 10 μM ODQ) were used to distinguish between NO and EDHF-mediated relaxation. Superoxide anion levels were assessed by L-012 and lucigenin enhanced-chemiluminescence techniques. Incubation of mesenteric rings with high glucose for 2 h caused a significant increase in superoxide anion generation and a significant impairment of endothelium-dependent relaxation. Exendin-4 and DPP-4 inhibitor linagliptin, but not sitagliptin or vildagliptin, significantly reduced vascular superoxide and improved endothelium-dependent relaxation in the presence of high glucose. The beneficial actions of exendin-4, but not linagliptin, were attenuated by the GLP-1R antagonist exendin fragment (9-39). Further experiments demonstrated that the presence of high glucose impaired the contribution of both nitric oxide and endothelium-dependent hyperpolarisation to relaxation and that linagliptin improved both mechanisms involved in endothelium-dependent relaxation. These findings demonstrate that high glucose impaired endothelium-dependent relaxation can be improved by exendin-4 and linagliptin, likely due to their antioxidant activity and independently of any glucose lowering effect.
authors.affiliation: School of Medical Sciences, RMIT University, Melbourne, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Salheen
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, New South Wales, Australia.
authors.forename: U
authors.initials: U
authors.lastname: Panchapakesan
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, New South Wales, Australia.
authors.forename: C A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: School of Medical Sciences, RMIT University, Melbourne, Australia. Electronic address: owen.woodman@rmit.edu.au.
authors.forename: O L
authors.initials: OL
authors.lastname: Woodman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004727:Endothelium / Q000187:drug effects*; D000077270:Exenatide; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D000069476:Linagliptin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D011748:Pyrogallol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000975:Antioxidants; D001685:Biological Factors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010455:Peptides; D014688:Venoms; C067410:endothelium-dependent hyperpolarization factor; D011748:Pyrogallol; D013481:Superoxides; D000069476:Linagliptin; D000077270:Exenatide; D005947:Glucose; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Dipeptidylpeptidase-4 inhibitors; Endothelium-dependent relaxation; Exendin-4; High glucose; Superoxide anion