REGULATION OF GLUCAGON-LIKE PEPTIDE-1-(7-36) AMIDE, PEPTIDE YY, AND NEUROTENSIN SECRETION BY NEUROTRANSMITTERS AND GUT HORMONES IN THE ISOLATED VASCULARLY PERFUSED RAT ILEUM

Neurotensin (NT), peptide YY (PYY), and several peptides derived from proglucagon are promptly released from endocrine cells of the distal p art of the gut after oral ingestion of a meal, thus suggesting that re lease of these peptides is partly under neural and/or hormonal control . Our previous studies conducted with a model of isolated vascularly p erfused rat colon showed that colonic L cells are highly responsive to several transmitters of the gut and to the hormonal peptide GIP. To t est the possibility that hormones produced by the proximal small intes tine or transmitters of the enteric nervous system may also modulate t he secretory activity of the ileal L cells, various intestinal regulat ory peptides and neurotransmitters were administered intraarterially f or 30 min in the isolated vascularly perfused rat ileum preparation. T he secretory activity of the ileal N cells was comparatively assessed. The release of NT, PYY, and glucagon-like peptide-1 (GLP-1) in the po rtal effluent was measured with specific RIAs. The muscarinic choliner gic agonist bethanechol at a concentration of 10(-4) M provoked a biph asic release of PYY, GLP-1, and NT, consisting of an early peak follow ed by a sustained response. Similarly, bombesin (10(-7) M) induced a m arked biphasic release of PYY and GLP-1. In contrast, the NT response was essentially monophasic, characterized by an early peak secretion. Tetrodotoxin did not modify the bombesin-induced release of PYY, GLP-1 , and NT. The beta-adrenergic agonist isoproterenol at a concentration of 10(-6) M induced a transient rise in portal PYY and GLP-1 concentr ations, whereas the effect on NT release was clearly biphasic. Calcito nin gene-related peptide (5 X 10(-8) M) induced a dramatic rise in PYY , GLP-1, and NT immunoreactivities in the portal effluent (peaks at 60 0%, 500%, and 550% of the basal values, respectively, 4 min after the start of infusion). Intraarterial infusion of GIP over the concentrati on range (0.5-3 nM) evoked a significant increase in portal concentrat ion of the three peptides only at the threshold concentration of 3 nM. Secretin (50 pM) or cholecystokinin (50 pM) did not affect the releas e of ileal hormones. In conclusion, ileal L and N cells respond to a v ariety of transmitters of the gut. The pattern of peptide release depe nds on the cell type studied. The two cosynthesized peptides, PYY and GLP-1, appear to be cosecreted in the conditions of the present study. Surprisingly, the ileal L cells do not respond to physiological conce ntrations of GIP that were previously shown to induce a release of bot h PYY and GLP-1 in the isolated vascularly perfused rat colon preparat ion. Together, these results suggest regional differences in the sensi tivity of L cells to neurotransmitters and gut hormones.