Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
Department of Vascular Surgery, Aalborg University Hospital, Aalborg, Denmark.
Br J Pharmacol. 2019 Feb;176(3):386-399. doi: 10.1111/bph.14534. Epub 2018 Dec 9.
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.
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.
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.
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.
胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素激素，它以葡萄糖依赖的方式调节胰岛素的生物合成和分泌，并且已被报道具有血管舒张作用。在这里，我们研究了 GLP-1 的可能血管舒张作用及其潜在机制。
将大鼠肠系膜动脉（直径≈200-400μm）和人皮下动脉安装在微血管张力记录器中进行等长张力记录。在正常血糖浓度和高血糖浓度下，检查 GLP-1 对血管反应的影响。
在无分支的大鼠肠系膜动脉和人皮下动脉中，生理浓度（1-100nM）的 GLP-1（7-36）和利拉鲁肽均不能引起舒张或影响电刺激引起的收缩。与 GLP-1（7-36）相反，利拉鲁肽引起的舒张作用可被 GLP-1 受体拮抗剂 exendin-(9-39)拮抗分支肠系膜动脉中的。与利拉鲁肽相反，GLP-1 使来自外周动脉疾病患者的皮下动脉中缓激肽的浓度舒张曲线向左移动，这种作用对 exendin-(9-39)具有抗性。在正常血糖浓度下，GLP-1 或利拉鲁肽均不影响大鼠肠系膜动脉中 ACh 的舒张。在暴露于 40mM 葡萄糖的动脉中，与利拉鲁肽相反，GLP-1 通过一种不受 exendin-(9-39)拮抗的机制增强了 ACh 诱导的舒张作用。GLP-1 降低了暴露于 40mM 葡萄糖的大鼠肠系膜动脉中用二氢乙啶测量的超氧化物水平。
在正常血糖条件下，GLP-1 受体参与利拉鲁肽引起的分支动脉舒张，而 GLP-1 抑制血管超氧化物水平有助于 GLP-1 受体非依赖性增强高血糖时内皮依赖性血管舒张。
