Different mechanisms involved in liraglutide and glucagon-like peptide-1 vasodilatation in rat mesenteric small arteries

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner, and has been reported to induce vasodilatation. Here, the aim was to examine the possible vasorelaxant effect of GLP-1 and the underlying mechanisms.

EXPERIMENTAL APPROACH: Rat mesenteric arteries (diameter ≈ 200-400 μm) and human subcutaneous arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined at normoglycemic conditions and at high glucose.

KEY RESULTS: In rat mesenteric arteries and human subcutaneous arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation, or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39) in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted concentration relaxation curves for bradykinin in subcutaneous arteries from patients with peripheral arterial disesase, an effect insensitive to exendin-(9-39). In normoglycemic conditions neither GLP-1 nor liraglutide changed acetylcholine relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated acetylcholine-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose.

CONCLUSION AND IMPLICATIONS: Our findings suggest that a GLP-1 receptor-dependent mechanism is involved in liraglutide relaxation in branched arteries in normoglycemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycemia.