Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism

Nyström, Thomas; Gonon, Adrian; Sjöholm, Åke; Pernow, John

doi:10.1016/j.regpep.2004.08.024

Cited by 168 publications

(131 citation statements)

References 15 publications

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“…A common mediator of vascular relaxation is NO, released from endothelial cells via conversion of L-arginine by NO synthase. However, in this study neither endothelial denudation nor inhibition of NO by L-NAME affected GLP-1-induced relaxation, findings which are supported by an earlier study in rat femoral artery [16]. Cyclooxygenase converts arachidonic acid to its prostanoid metabolites, many of which have vasodilatory properties.…”

Section: Discussionsupporting

confidence: 83%

“…Exendin (9-39) is a well characterised antagonist of the GLP-1 receptor which has been demonstrated on numerous occasions to block the biological actions of both GLP-1(7-36)amide and exendin-4 (1-39) [20,21,23,[25][26][27]. Indeed, a previous study on the ex vivo vascular actions of GLP-1 reported that exendin (9-39) significantly inhibited GLP-1-induced relaxations in rat femoral artery [16]. However, in the present investigation we clearly demonstrated that this pep- ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies investigating the ex vivo vascular actions of GLP-1 in rat blood vessels have suggested that it causes direct relaxation via an endothelium-independent mechanism [15,16]. The aim of the present study was to significantly extend these preliminary findings to a detailed investigation of the mechanisms by which native GLP-1(7-36)amide, three structurally-related peptides (GLP-1(9-36)amide, exendin-4 (1-39) and exendin (9-39)) and a small molecule GLP-1 receptor agonist, may modulate vascular function.…”

Section: T R a C Tmentioning

confidence: 99%

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

Green

Hand

Dougan

et al. 2008

Archives of Biochemistry and Biophysics

138

133

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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.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: T R a C Tmentioning

confidence: 99%

See 1 more Smart Citation

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

Green

Hand

Dougan

et al. 2008

Archives of Biochemistry and Biophysics

138

133

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“…Recent evidence suggests that GLP-1 regulates endothelial function. GLP-1 relaxed femoral artery in a dose-response manner (23), and GLP-1 is associated with vasodilation induced by acetylcholine (24). In humans, the systemic infusion of GLP-1 or its analogs does not induce hypertension but, rather, has protective effects (25,26).…”

Section: Discussionmentioning

confidence: 97%

Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity

et al. 2008

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OBJECTIVE-To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.RESEARCH DESIGN AND METHODS-Awake free-moving mice were infused with the GLP-1 receptor agonist exendin-4 (Ex4) into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu-/hyperglycemic clamps. Arterial femoral blood flow, whole-body insulin-stimulated glucose utilization, and heart rates were continuously recorded. RESULTS-A continuous 3-h brain infusion of Ex4 decreasedfemoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemichyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) antagonist exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4-infused mice, which disappeared in Ex9 and GLP-1R knockout mice. Moreover, hypothalamic nitric oxide synthase activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R-dependent manner, whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity, and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.CONCLUSIONS-Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.

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“…GLP-1 also promotes endotheliumindependent artery relaxation [26], and may increase diuresis and natriuresis, suggesting a possible renal protective effect [27,28]. Furthermore, there is evidence that the synthetic GLP-1 receptor agonists may reduce systolic blood pressure and triglyceride levels and have beneficial effects on markers of cardiovascular risk, such as plasminogen activator inhibitor (PAI-1) and brain natriuretic peptide (BNP) [29].…”

Section: Hormonal and Metabolic Abnormalities In The Pathogenesis Of mentioning

confidence: 99%

Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

Pratley¹,

Gilbert²

2008

Rev Diabet Stud

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■ AbstractUntil recently, the pathogenesis of type 2 diabetes mellitus (T2DM) has been conceptualized in terms of the predominant defects in insulin secretion and insulin action. It is now recognized that abnormalities in other hormones also contribute to the development of hyperglycemia. For example, the incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is attenuated in T2DM. Intravenous administration of GLP-1 ameliorates hyperglycemia in patients with T2DM, but an extremely short half-life limits its utility as a therapeutic agent. Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.

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Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism

Cited by 168 publications

References 15 publications

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

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

Brain Glucagon-Like Peptide-1 Regulates Arterial Blood Flow, Heart Rate, and Insulin Sensitivity

Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

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