GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP

Abstract

a b s t r a c tIncreasing evidence from both clinical and experimental studies indicates that the insulin-releasing hormone, glucagon-like peptide-1 (GLP-1) may exert additional protective/reparative effects on the cardiovascular system. The aim of this study was to examine vasorelaxant effects of GLP-1(7-36)amide, three structurally-related peptides and a non-peptide GLP-1 agonist in rat aorta. Interestingly, all GLP-1 compounds, including the established GLP-1 receptor antagonist, exendin (9-39) caused concentrationdependent relaxation. Mechanistic studies employing hyperpolarising concentrations of potassium or glybenclamide revealed that these relaxant effects are mediated via specific activation of ATP-sensitive potassium channels. Further experiments using a specific membrane-permeable cyclic AMP (cAMP) antagonist, and demonstration of increased cAMP production in response to GLP-1 illustrated the critical importance of this pathway. These data significantly extend previous observations suggesting that GLP-1 may modulate vascular function, and indicate that this effect may be mediated by the GLP-1 receptor. However, further studies are required in order to establish whether GLP-1 related agents may confer additional cardiovascular benefits to diabetic patients.

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

“…Notably, EX4 did not produce vasodilatation or cGMP release in that preparation (1). In comparison, GLP-1 induced vasorelaxation in the rat aorta through classic GLP-1R-dependent AC-coupled mechanisms (19). Here we show that the effect of EX4 on GFR and, thus potentially on the renal vasculature, is dependent on an intact GLP-1R.…”

Rapid and Body Weight–Independent Improvement of Endothelial and High-Density Lipoprotein Function After Roux-en-Y Gastric Bypass

“…33 Physiologically, GLP-1 promotes endothelial health indirectly by triggering insulin production 38 and by activating its own endothelial signaling pathways. 32,34,35 The present findings demonstrate that increased plasma levels of GLP-1 after RYGB activate GLP-1 receptor-dependent intracellular signaling and induce a rapid restoration of endothelium-dependent relaxations. These beneficial effects were independent of weight because they were absent in rats that had a weight loss matched to RYGB.…”

GLP 1 and Macrovascular Complications

“…Interestingly, this same experiment showed a preserved vasodilatory effect of GLP1 and its metabolite in the absence of a functional GLPR (GLPR-/-mice), suggesting a GLP1R independent pathway. It is also worth noting, that exendin 4 treatment had no vasodilatory effect in the phenylephrine preconstricted rat mesenteric arteries [43]. In support to GLP1 vasodilatory ability, Green et al conducted a study on phenylephrine preconstricted rat thoracic aortic rings.…”