title: High-affinity CCK-A receptors on the vagus nerve mediate CCK-stimulated pancreatic secretion in rats.
abstract: Cholecystokinin (CCK) receptors are found on vagal afferent fibers. In pancreatic acini, CCK receptors exist in high- and low-affinity states. The aim of this study was to identify the vagal CCK-A receptor affinity state that mediates the effect of CCK on pancreatic protein secretion. Using a rat model with a pancreatic-biliary cannula, we studied the effects of CCK-JMV-180 on exocrine pancreatic function. CCK-JMV-180 acts as an agonist on high-affinity CCK receptors and as an antagonist on low-affinity CCK receptors. Infusion of CCK-JMV-180 (22-88 micrograms.kg-1.h-1) caused dose-dependent increases in pancreatic protein secretion, which were blocked by the CCK-A receptor antagonist L-364,718. Acute vagotomy in anesthetized rats and perivagal application of capsaicin in conscious rats abolished pancreatic responses to CCK-JMV-180 at 22 and 44 micrograms.kg-1.h-1. CCK-JMV-180 did not reduce pancreatic responses to CCK octapeptide infusion at 20 and 40 pmol.kg-1.h-1. To demonstrate that endogenously released CCK also acts on high-affinity CCK-A receptors, we showed that in conscious rats intraduodenal infusion of 18% casein produced a threefold increase in protein secretion and elevated plasma CCK levels from 0.7 to 8.4 pM. Infusion of CCK-JMV-180 at 44 micrograms.kg-1.h-1 failed to inhibit pancreatic responses to casein. In separate studies, perivagal application of 1% capsaicin inhibited 95% and 90% of the pancreatic responses to casein and casein combined with intravenous CCK-JMV-180, respectively. The neurotoxic effect of capsaicin on small-diameter sensory vagal fibers was verified by immunohistochemical and retrograde tracing studies. In conclusion, we demonstrated that in contrast to their effect on satiety, which is mediated by vagal low-affinity CCK-A receptors, exogenous CCK and endogenous CCK under physiological conditions act through high-affinity CCK-A receptors to mediate pancreatic protein secretion. These findings suggest that different affinity states of the vagal CCK receptors mediate different digestive functions.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Hao
authors.forename: C
authors.initials: C
authors.lastname: Owyang
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002364:Caseins / Q000008:administration & dosage / Q000494:pharmacology; D020109:Devazepide; D004386:Duodenum / Q000294:innervation / Q000502:physiology; D018738:Hexamethonium / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000502:physiology*; D012844:Sincalide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
chemical_list: D001570:Benzodiazepinones; D002364:Caseins; D006727:Hormone Antagonists; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C058451:JMV 180; D018738:Hexamethonium; D001285:Atropine; D020109:Devazepide; D012844:Sincalide; D002211:Capsaicin