Action of GLP-1 (7-36) amide and exendin-4 on Suncus murinus (house musk shrew) isolated ileum

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists have been reported to modulate gastrointestinal motility but the mechanism is essentially unknown. In the present studies, we investigated the potency and mechanism of action of GLP-1 receptor ligands on the isolated ileum of Suncus murinus, an insectivore used in anti-emetic research. Ileal segments were mounted in organ baths containing Kreb's solution. Cumulative concentration–response curves to GLP-1 (7-36) amide (0.1–300 nM) and exendin-4 (0.1–100 nM) were constructed in the absence and presence of exendin (9-39) amide (0.3–3 nM). GLP-1 (7-36) amide and exendin-4 induced concentration-dependent contractions yielding pEC₅₀ values of 8.4 ± 0.2 and 8.4 ± 0.4, respectively. Exendin (9-39) antagonized the action of both agonists in a non-competitive reversible manner, with apparent pK_B values of 9.5 and 9.7, respectively. Tetrodotoxin (1 μM), atropine (1 μM) and hexamethonium (500 μM) were used to determine the contractile mechanism of action of exendin-4. Tetrodotoxin and atropine significantly antagonized (P < 0.01) the contractile action of exendin-4 (10 nM); hexamethonium (500 μM) had no action. These studies suggest that GLP-1 receptor agonists contract the ileum indirectly via postganglionic enteric neurones and an involvement of muscarinic receptors. These studies provide information relevant to the use of this species to estimate the therapeutic indexes of GLP-1 receptor agonists.