Experiments are proposed to study the basic electrophysiological and neural regulation of the gastroduodenal junction. This region of the gastrointestinal tract, which includes the distal antrum, pyloric sphincter, and proximal duodenum, is thought to be important in controlling the rate at which gastric contents are emptied into the small intestine. Its physiology is complicated and has not been fully described by previous extracellular electrical recordings and whole- animal studies. Cross-sectional strips of the pyloric muscularis and isolated smooth muscle cells have been developed to allow precise studies of the ionic mechanisms of the effects of neurotransmitters. Experiments characterizing the ionic conductances expressed by pyloric muscle cells will determine the reasons for the heterogeneity in the electrical activity recorded at different depths through the muscularis. Using intact muscles, the effects of cholinergic, non- adrenergic-non-cholinergic (NANC), and non-cholinergic excitatory nerves on electrical and mechanical activities will be characterized. After characterizing the effects of putative neurotransmitters on intact muscles, patch clamp studies will be performed to study the specific conductances activated by each agent. Preliminary evidence suggests that cholinergic and non-cholinergic excitatory transmitters function via the activation of a non-selective cation conductance, while NANC transmitters activate potassium conductances. These studies will be particularly useful because they will reveal specific ion channel proteins that could be targeted in attempts to develop therapeutic agents to control abnormal pyloric sphincter function. Studies will also be performed to determine the factors that regulate the release of neurotransmitters. Recent work has shown that nitric oxide may mediate a portion of the NANC neurotransmission in the gastroduodenal junction. Morphological studies will investigate the innervation by nerves that express nitric oxide synthase, and experiments will attempt to determine the 2nd messenger systems activated by nitric oxide stimulation. Biochemical studies will measure nitric oxide release and the effects of this on cyclic nucleotide levels. These studies, using a variety of technologies, will provide an overview of the basic electrical and neural control mechanisms that regulate the motility of the gastroduodenal junction and may help to explain the role of the pylorus in regulating gastric emptying.
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