During the previous funding period, we documented that duodenal pH plays a critical role in regulating gastric motility. In healthy subjects, lowering of duodenal pH inhibits gastric contractions and prevents the occurrence of the interdigestive migrating motor complex via the release of secretin which inhibits gastric motility. This mechanism may be important in protecting the duodenum from excessive amounts of acid. In patients with a history of duodenal ulcer, we showed that duodenal acidification fails to inhibit gastric motor activity due to impaired action of secretin. We have demonstrated that secretin stimulates vagal afferent neurons. Thus it is likely that this abnormality in duodenal ulcer patients may be secondary to malfunctioning of the vagal afferent pathway. A logical first step to identify this abnormality is to establish the mechanisms and sites of action of secretin to mediate gastric motility. We hypothesize that, at physiologic concentrations, secretin acts on vagal afferent neurons to stimulate vagal motor neurons culminating in the release of VIP, which induces gastric relaxation via a prostaglandin-dependent pathway. To test this hypothesis, we will use a rat model and employ a vertically integrated experimental design utilizing a variety of methods. We plan to investigate the effects of vagal rootlet section on the inhibitory action of exogenous and endogenous secretin in rats. To localize the vagal branches responsible for secretin's action of exogenous and endogenous secretin in rats. To localize the vagal branches responsible for secretin's action, chemical ablation with capsaicin of specific subdiaphragmatic vagal branches will be performed. The secretin receptors on vagal afferent fibers will be characterized with receptor autoradiography studies in both intact as well as capsaicin treated rats. Receptor densities and affinity will be studied using Scathard analysis under various experimental conditions to activate the G proteins and protein kinase C. To provide direct electrophysiological evidence that secretin stimulates vagal afferent pathway, single afferent fiber recording will be performed to characterize secretin's action. Neurotransmitters in specific secretin sensitive neurons in the nodose will be identified by intracellular recording and labeling techniques. In separate studies we will characterize the vagal efferent pathway mediating secretin's action. The role of VIP vs nitric oxide will be examined and the involvement of prostaglandins to mediate secretin's action will be assessed. The cellular mechanisms by which VIP stimulates prostaglandin will be studied. These studies will provide a detailed mechanistic study of secretin's action on gastric motility and improve our understanding of the vagal control of gastric motility in general.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine A Subcommittee 2 (GMA)
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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