MECHANISM OF NEUROTENSIN STIMULATION OF EXTERNAL PANCREATIC-SECRETIONIN THE RAT

The gut and brain peptide neurotensin has been claimed to directly or indirectly stimulate external pancreatic secretion. The purpose of thi s study was to analyze the mechanism of the neurotensin effect on exte rnal pancreatic secretion in the rat. The pancreatic dose-response cur ve to 40-min venous infusions of neurotensin 1-13 (0.1-10 mug/kg-h = 0 .06-6 nmol/kg-h) was biphasic; the maximal response occurred at 3.16 m ug/kg-h and reached approximately 30% of the maximal response to chole cystokinin (CCK). The ED50 was 0.27 mug/kg-h (= 0. 16 nmol/kg-h) for b icarbonate and 0.45 mug/kg-h (= 0.27 nmol/kg-h) for protein output. Pa ncreatic secretion in response to each neurotensin dose increased stea dily during the infusion and peaked 20-40 min after the end of infusio n. Atropine and hexamethonium suppressed the stimulatory effect of neu rotensin on volume, bicarbonate, and total protein output (p < 0.01). The CCK(A) receptor antagonist L364718 decreased by 80% sodium and bic arbonate response (p < 0.01) and suppressed protein response (p < 0.01 ) to neurotensin. Methadone reduced the response to neurotensin by 85% , vagotomy by 80%, and capsaicin pretreatment by 70%. The blockade of alpha1-, alpha2-, and beta-adrenoreceptors or of CCK(B) receptors did not change the neurotensin effect. We conclude that the mechanism of n eurotensin stimulation is indirect and neurally mediated and involves nicotinic and muscarinic synapses, CCK(A) receptors, and, in part, cap saicin-sensitive sensory fibers. This suggests that neurotensin activa tes receptors present on peripheral afferent fibers and that this info rmation is built up in a central reflex loop involving, in part, CCK(A ) receptors and is conveyed to the pancreas by a cholinergic vagal eff erent pathway.