Effect of Glucagon-Like Peptide-1(7–36) and Exendin-4 on the Vascular Reactivity in Streptozotocin/Nicotinamide-Induced Diabetic Rats

Abstract

We investigated the vascular effects of glucagon-like peptide-1 (GLP-1) and Exendin-4 in type 2 diabetic rat aortae. Studies were performed in a normal control group (NC) (0.2 ml i.p. saline, n = 10), streptozotocin (STZ)/nicotinamide diabetic control group (DC) (a single dose of 80 mg/kg STZ i.p. injection 15 min after administration of 230 mg/kg nicotinamide i.p.), GLP-1 (GLPC) control group (1 µg/kg twice daily i.p. for 1 month, n = 10), Exendin-4 control group (EXC) (0.1 µg/kg twice daily i.p. for 1 month, n = 10), GLP-1-treated diabetic group (GLPT) (1 µg/kg twice daily i.p. for 1 month, n = 10), and Exendin-4-treated diabetic group (EXT) (0.1 µg/kg twice daily i.p. for 1 month, n = 10). One month of GLP-1 and Exendin-4 treatment significantly decreased the blood glucose levels of diabetic rats (113 ± 2 mg/dl, p < 0.001, and 117 ± 1 mg/dl, p < 0.001, respectively versus 181 ± 9 mg/dl in the DC group). Sensitivity (pD₂) and maximum response (% Max. Relax) of acetylcholine-stimulated relaxations in the DC group (pD₂: 6.73 ± 0.12 and 55 ± 6, respectively) were decreased compared with the non-diabetic NC group (pD₂: 7.41 ± 0.25, p < 0.05, and 87 ± 4, p < 0.01). Treating diabetic rats with GLP-1, pD₂ values and with Exendin-4, Max. Relax %values of aortic strips to acetylcholine returned to near non-diabetic NC values (pD₂: 7.47 ± 0.15, p < 0.05, and 87 ± 3, p < 0.01, respectively). Maximal contractile responses (E_max) to noradrenaline in aortic strips from the diabetic DC group (341 ± 27 mg tension/mg wet weight) were significantly decreased compared with the non-diabetic NC (540 ± 66 mg tension/mg wet weight, p < 0.001) and the GLPT group (490 ± 25 mg tension/mg wet weight, p < 0.05). There were no significant differences in pD₂ values of aortic strips to noradrenaline from all groups. E_max to KCl in aortic strips from the DC group (247 ± 10 mg tension/mg wet weight, p < 0.01) was significantly decreased compared with non-diabetic NC group (327 ± 26 mg tension/mg wet weight). Treating diabetic rats with GLP-1 (GLPT), E_maxvalues of aortic strips to KCl returned to near non-diabetic NC values (271 ± 12 mg tension/mg wet weight). GLP-1 and (partially) Exendin-4 treatment could improve the increased blood glucose level and normalize the altered vascular tone in type 2 diabetic rats.

Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis

“…After 7 days, animals received vehicle or a single intraperitoneal injection of CCl 4 , 0.4 ml per 100 g body weight (50% mineral oil:CCl 4 ), which triggers cholangiocyte cell death by apoptosis 20. Subsequently, animals were treated with either (1) exendin-4 (0.1 μg/kg body weight twice a day, intraperitoneally, n = 8) or (2) control injections (n = 8) 9 21. Rats subjected to BDL, injected with vehicle and treated with control solution were used as internal controls (n = 4).…”

Cardiovascular and hemodynamic effects of glucagon-like peptide-1

“…Although there is reason to question immunodetection of GLP-1R expression using antibody-based methodologies available prior to 2013 [55], there is considerable evidence that GLP-1R is functionally expressed in the endothelium, as activation with GLP-1 (7-36), GLP-1R agonists, or DPP-4 inhibitors results in phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, production of nitric oxide, and suppression of endothelin-1 expression [53, 56–59]. Studies in isolated aorta [60, 61], pulmonary arteries [62], and rodent hearts [12, 16] also support that GLP-1 mediates vasodilation via an endothelial-dependent mechanism. Signaling pathways implicated in these endothelial effects of GLP-1 include AMPK [56] and cAMP/PKA-PI3K/Akt dependent activation of K ATP channels (Summarized in Figure 1) [51, 59, 61, 63].…”

Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial

“…In a diabetic rat model it was shown that GLP-1 infusion nearly re-established normal vascular tone of aortic strips [9]. Moreover, in vitro studies revealed that DPP-4 is expressed in endothelial cells and that inhibition of DPP-4 reduced the microvascular tone through direct mediation of the NO system [10].…”