The long-term objectives of this application are to understand the physiology and pathophysiology of esophageal motor disorders causing heartburn, chest pain and difficulty in swallowing and to identify targets for their drug therapy. Specific studies will be performed on the opossum esophagus to study the neurotransmitters and the ion channels involved in the electromechanical nd pharmacomechanical coupling in esophageal peristalsis and lower esophageal sphincter tone and relaxation. Studies will be performed in each of the three esophageal muscle groups, namely, esophageal circular muscle, longitudinal muscle and lower esophageal sphincter muscle. Parallel studies will be performed as follows: (i) patch-clamp whole-cell recordings will be done using freshly dispersed esophageal smooth muscle cells for the identification and characterization of K+, Cl- and Ca2+ channels which may be involved in the action of inhibitory and excitatory neurotransmitters. (2) intracellular microelectrode recordings from muscle strips in vitro will be performed to identify the inhibitory and excitatory neurotransmitters (nitric oxide (NO), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), substance P (SP) and acetylcholine (ACh)], postjunctional receptor subtypes and ion conductances involved in their actions on the smooth muscle; (3) intracellular microelectrode recordings from muscle strips in vitro will be performed to identify the neurotransmitters involved in the inhibitory and excitatory actions of nerves in the esophagus. The neurotransmitters listed in (2) will be investigated specifically; (4) morphological studies will be undertaken to determine the chemical nature of intramural neurons using histochemistry and immunocytochemistry to provide an anatomic substratum for the foregoing functional studies; (5) studies will be performed on the effects of agonists and antagonists of neurotransmitters and ion channels in anesthetized animals to understand esophageal physiology, pathophysiology and potential therapies in intact animal models; and (6) functional and morphological studies will be done on discarded human esophageal tissues removed to surgery to test directly in human material the hypotheses generated from animal studies. This integrated continuation of our ongoing investigations offers a cost- effective approach to an understanding of the physiology and pathophysiology of esophageal motor disorders and to identifying new targets for therapy of these disorders.
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