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

Green, Brian D.; Hand, Katharine; Dougan, Janette E.; McDonnell, Bronagh; Cassidy, Roslyn; Grieve, David

doi:10.1016/j.abb.2008.08.001

Cited by 138 publications

(151 citation statements)

References 40 publications

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“…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.…”

Section: Discussionmentioning

confidence: 68%

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

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

132

111

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Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na ϩ reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na ϩ excretion, and renal membrane expression of the Na ϩ /H ϩ exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na ϩ reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.glucagon-like peptide-1; dipeptidyl peptidase-4; NHE3; cAMP; proximal tubule GLUCAGON-LIKE PEPTIDE -1 (GLP-1), an incretin hormone secreted from enteroendocrine L cells in the intestine, stimulates glucose-dependent insulin release and may promote preservation of beta-cell function in patients with type 2 diabetes (9, 10). As a consequence, GLP-1 has been a principal focus of clinical and basic diabetes research in recent years. After secretion, active GLP-1 is rapidly cleaved by the widely expressed enzyme dipeptidyl peptidase-4 (DPP-4, CD26), such that the half-life of bioactive GLP-1 is Ͻ3 min. Therefore, therapeutic manipulation of the GLP-1 system includes strategies that inhibit the degradation of GLP-1 by DPP-4 (i.e., DPP-4 inhibitors) or degradation-resistant GLP-1 receptor (GLP-1R) agonists with a longer half-life, such as exendin-4 (EX4) or liraglutide.In addition to its metabolic effects, GLP-1 affects kidney function. Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6, 30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in...

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Section: Discussionmentioning

confidence: 68%

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

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

132

111

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“…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.…”

Section: Improved Endothelium-dependent Relaxations After Rygb Involvmentioning

confidence: 74%

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

et al. 2015

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O besity is a worldwide health problem because of the associated increased morbidity and cardiovascular mortality. Accompanying metabolic disorders such as insulin resistance and type 2 diabetes mellitus and risk factors such as dyslipidemia increase the disease risk linked to obesity. In particular, obesity induces endothelial dysfunction, which precedes atherosclerosis, but also contributes to insulin resistance in tissues Background-Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight lossindependent manner. The present study investigated in rats and patients whether obesity-induced endothelial and highdensity lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. Methods and Results-Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin 9-39 (10 μg·kg). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDLmediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. Conclusions-RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity. Furthermore, obesity and insulin resistance result in proatherogenic dyslipidemia, 4 characterized by high low-density lipoprotein and triglyceride and low high-density lipoprotein (HDL) cholesterol plasma levels.1,5 Abnormal HDL remodeling and maturation have been reported in obese subjects with an HDL profile similar to that of subjects with established cardiovascular disease. 5 In addition, pathological situations associated with obesity, in particular type 2 diabetes mellitus 6 and coronary artery disease, 7 impair the physiological protective properties of HDL, which preserves en...

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“…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.…”

Section: Glp1 and Peripheral Vascular Diseasementioning

confidence: 99%

GLP 1 and Macrovascular Complications

Sleiman¹,

Azar²

2011

J Diabetes Metab

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Type two diabetes remains to be one of the most challenging chronic diseases affecting 26 million people in the United States. Despite advances in the management of this illness, a large number of diabetics suffer from disease related complications. Heart disease and stroke account for a significant percentage of death in diabetics. Advancing treatment options for diabetics beyond glycemic control and Hba1c levels to prevent macrovascular complications should be the target of our management. GLP1, a member of the pro-glucagon incretin family, and GLP1 analogues seems to have beneficial effects on the macrovascular levels, in addition to their established effect on the glycemic control. This article reviews the potential effect of GLP1 family on the macrovascular complications including cardiovascular, cerebrovascular, and peripheral vascular diseases.

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

Cited by 138 publications

References 40 publications

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

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

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

GLP 1 and Macrovascular Complications

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