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

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  • Maj Bangshaab
  • Alejandro Gutierrez
  • Khiem Dinh Huynh
  • Jakob Schöllhammer Knudsen
  • Daniel Dias Rufino Arcanjo
  • Asbjørn G Petersen
  • Jørgen Rungby
  • Michael Gejl
  • Ulf Simonsen
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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.

OriginalsprogEngelsk
TidsskriftBritish Journal of Pharmacology
Vol/bind176
Udgave nummer3
Sider (fra-til)386-399
Antal sider14
ISSN0007-1188
DOI
StatusUdgivet - 1 feb. 2019

ID: 56675457