vasoactive-intestinal-peptide and glucagon-like-peptide-1-(7-36)amide

The gastrointestinal peptides glucagon-like peptide-1(7-36)amide (GLP-1) and amylin are currently being tested in clinical trials for the treatment of diabetes mellitus due to their effects in lowering blood glucose. Receptors for these polypeptides also exist in the lung and since polypeptides are known to modulate airway and pulmonary vascular tone, we investigated whether GLP-1 and amylin act similarly in the lung. We compared their effects with the well-known actions of calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP). Both GLP-1 and amylin induced a dose-dependent and time-reversible endothelial-dependent relaxation of preconstricted pulmonary artery rings. Amylin was approximately as strong as VIP and CGRP, GLP-1 however, was 2.3-fold less potent. GLP-1 as well as amylin also reduced the vascular tone in the isolated, perfused and ventilated rat lung. In contrast to their action on the pulmonary vasculature, neither GLP-1 nor amylin showed any effect on the tone of isolated preconstricted trachea rings. In conclusion, GLP-1 and amylin represent two additional peptides which may modulate pulmonary vascular tone.

Topics: Acetylcholine; Amyloid; Animals; Anti-Ulcer Agents; Calcitonin Gene-Related Peptide; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; In Vitro Techniques; Islet Amyloid Polypeptide; Male; Neurotransmitter Agents; NG-Nitroarginine Methyl Ester; Norepinephrine; Peptide Fragments; Perfusion; Pulmonary Artery; Pulmonary Circulation; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Trachea; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Topics: Animals; Bombesin; Colon; Dose-Response Relationship, Drug; Drug Synergism; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Guinea Pigs; In Vitro Techniques; Intestinal Mucosa; Ion Transport; Male; Neuropeptides; Peptide Fragments; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

Topics: Animals; Gastric Acid; Gastric Inhibitory Polypeptide; Gastric Mucosa; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Histamine; Histidine Decarboxylase; Male; Neurotransmitter Agents; Pentagastrin; Peptide Fragments; Rats; Rats, Wistar; Somatostatin; Vasoactive Intestinal Peptide

Glucagon-like peptide-1 7-36 amide (GLP-1) has been postulated to be the primary hormonal mediator of the entero-insular axis but evidence has been indirect. The discovery of exendin (9-39), a GLP-1 receptor antagonist, allowed this to be further investigated. The IC50 for GLP-1 receptor binding, using RIN 5AH beta-cell membranes, was found to be 0.36 nmol/l for GLP-1 and 3.44 nmol/l for exendin (9-39). There was no competition by exendin (9-39) at binding sites for glucagon or related peptides. In the anaesthetized fasted rat, insulin release after four doses of GLP-1 (0.1, 0.2, 0.3, and 0.4 nmol/kg) was tested by a 2-min intravenous infusion. Exendin (9-39) (1.5, 3.0, and 4.5 nmol/kg) was administered with GLP-1 0.3 nmol/kg, or saline, and only the highest dose fully inhibited insulin release. Exendin (9-39) at 4.5 nmol/kg had no effect on glucose, arginine, vasoactive intestinal peptide or glucose-dependent insulinotropic peptide stimulated insulin secretion. Postprandial insulin release was studied in conditioned conscious rats after a standard meal. Exendin (9-39) (0.5 nmol/kg) considerably reduced postprandial insulin concentrations, for example by 48% at 15 min (431 +/- 21 pmol/l saline, 224 +/- 32 pmol/l exendin, P < 0.001). Thus, GLP-1 appears to play a major role in the entero-insular axis.

Topics: Anesthesia; Animals; Arginine; Cells, Cultured; Consciousness; Eating; Fasting; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Infusions, Intravenous; Insulin; Insulin Secretion; Male; Pancreas; Peptide Fragments; Peptides; Protein Precursors; Radioligand Assay; Rats; Rats, Wistar; Receptors, Glucagon; Vasoactive Intestinal Peptide

Previous studies have demonstrated that glucagon-superfamily peptides stimulate insulin release from the pancreatic islets in a glucose dependent manner. In this study we have carried out a structure-activity study of their insulinotropic activity using a rat pancreas perfusion with 5.5 mM glucose concentration. The following peptides were examined: glucagon-like peptide-1(7-36)amide (tGLP-1), glucagon, gastric inhibitory peptide (GIP), peptide having an amino-terminal histidine and carboxy-terminal isoleucine amide (PHI), vasoactive intestinal polypeptide (VIP), growth hormone releasing factor(1-29)amide (GRF), GRF(1-27)amide and synthetic hybrid-peptides of PHI-GRF, PHI(1-11)-GRF(12-27) and PHI(1-20)-GRF(21-27). Their potencies were evaluated as: tGLP-1 = GIP > glucagon > PHI = VIP > PHI(1-20)-GRF(21-27) > PHI(1-11)-GRF(12-27) >> GRF(1-29) = GRF(1-27). It is clear that 0.1 nM tGLP-1 stimulated insulin release, whereas 1 microM GRF(1-29) did not. These results indicate that 1) in addition to N-terminal amino acid (histidine or tyrosine), position 4 (glycine), position 9 (aspartic acid) and position 11 (serine) in the amino acid sequence are important for their insulinotropic activity, 2) not only the N-terminal portion but also the C-terminal portion of these peptides contribute to their insulinotropic activity.

Topics: Amino Acid Sequence; Animals; Dose-Response Relationship, Drug; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Growth Hormone-Releasing Hormone; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Molecular Sequence Data; Peptide Fragments; Rats; Rats, Wistar; Sequence Homology, Amino Acid; Vasoactive Intestinal Peptide