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

TY - JOUR

T1 - Different mechanisms involved in liraglutide and glucagon-like peptide-1 vasodilatation in rat mesenteric small arteries

AU - Bangshaab, Maj

AU - Gutierrez, Alejandro

AU - Huynh, Khiem Dinh

AU - Knudsen, Jakob Schöllhammer

AU - Arcanjo, Daniel Dias Rufino

AU - Petersen, Asbjørn G

AU - Rungby, Jørgen

AU - Gejl, Michael

AU - Simonsen, Ulf

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/2

Y1 - 2019/2

N2 - 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, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms. Experimental Approach: Rat mesenteric arteries (diameter ≈ 200–400 μm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations. Key Results: In rat mesenteric arteries and human s.c. 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 the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-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. Conclusions and Implications: GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.

AB - 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, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms. Experimental Approach: Rat mesenteric arteries (diameter ≈ 200–400 μm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations. Key Results: In rat mesenteric arteries and human s.c. 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 the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-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. Conclusions and Implications: GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.

KW - ACTIVATION

KW - BLOOD-PRESSURE

KW - CONCISE GUIDE

KW - ENDOTHELIUM-DEPENDENT RELAXATION

KW - EXENATIDE

KW - GLP-1

KW - GLUCOSE

KW - PHARMACOKINETICS

KW - RECEPTOR AGONISTS

KW - RESISTANCE

U2 - 10.1111/bph.14534

DO - 10.1111/bph.14534

M3 - Journal article

C2 - 30403290

SN - 0007-1188

VL - 176

SP - 386

EP - 399

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 3

ER -