GLP-1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery

Department of Internal Medicine, Philipps University of Marburg, Germany.
The American journal of physiology (Impact Factor: 3.28). 11/1993; 265(4 Pt 1):L374-81.
Source: PubMed


Recent data revealed the existence of specific receptors for glucagon-like peptide-1(7-36)amide (GLP-1) on rat lung membranes. Utilizing slide-mount autoradiography of fresh frozen lung tissue sections, we have localized binding sites for GLP-1 on mucous glands in the trachea and on vascular smooth muscle of the pulmonary artery. When tracheas were incubated in a modified Ussing chamber, the addition of GLP-1 to the submucosal side increased 35S-sulfate-labeled macromolecule secretion (191 +/- 12% above basal, P < 0.005). The optimal secretory response elicited by GLP-1 was approximately 23% of the maximal secretory response after a maximal acetylcholine stimulation. Other proglucagon-derived peptides such as glucagon, oxyntomodulin, and GLP-2 had no effect. In isolated rings of arteries, GLP-1 (10(-8) to 10(-5) M) induced a dose-dependent and time-reversible relaxation of preconstricted arteries. In a preparation with denuded epithelium, GLP-1 lost its effect. In conclusion, GLP-1 might represent another neuropeptide that acts as neurotransmitter of the peptidergic, nonadrenergic-noncholinergic nervous system that innervates the airways.

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    • "In chronically instrumented rats in vivo, infusion of GLP-1(7-36) had regional hemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction but hindquarters vasodilatation (Gardiner et al., 2010). In isolated rat arteries in vitro, where metabolism would be expected to be minimized, GLP-1(7-36) causes both endothelium dependent and independent relaxation (Richter et al., 1993; Golpon et al., 2001; Ozyazgan et al., 2005; Nystrom et al., 2005; Green et al., 2008; Nathanson et al., 2009). Importantly, where studies compared both peptides, for example in rat aorta and femoral artery, GLP-1(9- 36) displays similar potency to GLP-1(7-36) (Green et al., 2008; Nathanson et al., 2009) consistent with similar potency of the two peptides in mouse aorta in this study albeit that the functional response that we observed was vasoconstriction. "
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    ABSTRACT: Aims : Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue, released in response to meal ingestion and efficiently lowers blood glucose in type 2 diabetic patients. GLP-1(7-36) is rapidly metabolized by dipeptidyl peptidase IV to the major metabolite GLP-1(9-36)-amide, often thought to be inactive. Inhibitors of this enzyme are widely used to treat diabetes. Our aim was to characterize the binding of GLP-1(9-36) to native mouse tissues and to cells expressing GLP1-R as well as to measure functional responses in the mouse aorta compared with GLP-1(7-36). Main methods : The affinity of [125I]GLP-1(7-36) and [125I]GLP-1(9-36) was measured in mouse tissues by saturation binding and autoradiography used to determine receptor distribution. The affinity of both peptides was compared in binding to recombinant GLP-1 receptors using cAMP and scintillation proximity assays. Vasoactivity was determined in mouse aortae in vitro. Key findings : In cells expressing GLP-1 receptors, GLP-1(7-36) bound with the expected high affinities (0.1 nM) and an EC50 of 0.07 nM in cAMP assays but GLP-1(9-36) bound with 70, 000 and 100,000 fold lower affinities respectively. In contrast, in mouse brain, both labeled peptides bound with a single high affinity, with Hill slopes close to unity, although receptor density was an order of magnitude lower for [125I]GLP-1(9-36). In functional experiments both peptides had similar potencies, GLP-1(7-36), pD2 = 7.40±0.24 and GLP-1(9-36), pD2 = 7.57±0.64. Significance : These results suggest GLP-1(9-36) binds and has functional activity in the vasculature but these actions may be via a pathway that is distinct from the classical GLP-1 receptor and insulin secretagogue actions.
    Life sciences 05/2014; 102(2). DOI:10.1016/j.lfs.2014.03.011 · 2.70 Impact Factor
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    • "However, the GLP-1R-expressing cell types that mediate these effects are not known, although recent studies showed atrial GLP-1R-mediated regulation of blood pressure in mice [11]. In addition, while lung Glp-1r mRNA expression is high in some species [12] and GLP-1R signaling is implicated in surfactant secretion [13]–[15], the role of GLP-1R in pulmonary function is not well established. Further, GLP-1 effects on adiposity and lipid metabolism are not completely understood. "
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    ABSTRACT: Class B G protein-coupled receptors (GPCRs) are important regulators of endocrine physiology, and peptide-based therapeutics targeting some of these receptors have proven effective at treating disorders such as hypercalcemia, osteoporosis, and type 2 diabetes mellitus (T2DM). As next generation efforts attempt to develop novel non-peptide, orally available molecules for these GPCRs, new animal models expressing human receptor orthologs may be required because small molecule ligands make fewer receptor contacts, and thus, the impact of amino acid differences across species may be substantially greater. The objective of this report was to generate and characterize a new mouse model of the human glucagon-like peptide-1 receptor (hGLP-1R), a class B GPCR for which established peptide therapeutics exist for the treatment of T2DM. hGLP-1R knock-in mice express the receptor from the murine Glp-1r locus. Glucose tolerance tests and gastric emptying studies show hGLP-1R mice and their wild-type littermates display similar physiological responses for glucose metabolism, insulin secretion, and gastric transit, and treatment with the GLP-1R agonist, exendin-4, elicits similar responses in both groups. Further, ex vivo assays show insulin secretion from humanized islets is glucose-dependent and enhanced by GLP-1R agonists. To enable additional utility, the targeting construct of the knock-in line was engineered to contain both flanking LoxP sites and a C-terminal FLAG epitope. Anti-FLAG affinity purification shows strong expression of hGLP-1R in islets, lung, and stomach. We crossed the hGLP-1R line with Rosa26Cre mice and generated global Glp-1r-/- animals. Immunohistochemistry of pancreas from humanized and knock-out mice identified a human GLP-1R-specific antibody that detects the GLP-1R in human pancreas as well as in the pancreas of hGLP-1r knock-in mice. This new hGLP-1R model will allow tissue-specific deletion of the GLP-1R, purification of potential GLP-1R partner proteins, and testing of novel therapeutic agents targeting the hGLP-1R.
    PLoS ONE 04/2014; 9(4):e93746. DOI:10.1371/journal.pone.0093746 · 3.23 Impact Factor
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    • "Both endogenous GLP-1 and exendin-4 induced vasorelaxation of the rat thoracic aorta via the involvement of ATP-sensitive potassium channels (KATP) and cyclic-adenosine monophosphate (cAMP) [3]. In rat femoral artery, GLP-1 caused endothelium-independent, dose-dependent relaxation [4], while in pulmonary arteries the vasodilation due to GLP-1 was described as endothelium-dependent [5,6]. GLP-1 was also described as elevating plasma nitric oxide (NO) levels, hence being a potent endothelial vasodilator [7]. "
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    ABSTRACT: It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S). We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger. Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation. Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance.
    Cardiovascular Diabetology 04/2014; 13(1):69. DOI:10.1186/1475-2840-13-69 · 4.02 Impact Factor
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