Esophageal reflux is a common condition that affects children and one in ten adults, and if untreated may result in chronic esophagitis, aspiration pneumonia, esophageal strictures, and Barretts esophagus, a premalignant condition. Although esophagitis is a multifactorial disease that may depend on inappropriate relaxation, speed of esophageal clearance, mucosal resistance and other factors, impairment of Lower Esophageal Sphincter (LES) pressure is a common finding in patients complaining of chronic heartburn. Preliminary data obtained in muscle strips and in single cells suggest that a) sphincter pressure, which is primarily myogenic and maintained by spontaneous contraction of the circular muscle layer, is mediated by continuous release of Ca++ from intracellular stores whereas esophageal contraction depends on influx of extracellular Ca++ through voltage- dependent Ca++ channels, b) damage to the mechanisms responsible for either storage or release of intracellular Ca++ may be the cause of the loss of LES tone observed after induction of experimental esophagitis. We now propose to define the mechanisms responsible for esophageal contraction and maintenance of LES tone in the normal esophagus and LES, and determine how they are affected in a model of experimental esophagitis. a) In the normal LES and esophagus we will examine the time course of Ca++ release and influx, the cycling of inositol phospholipids, and the effect of some putative calmodulin and protein kinase C antagonists on LES resting tone and on esophageal and LES contraction in response to agonists. These data will clarify the role of Ca++ and inositol phosphates in maintenance of normal LES and esophageal function, and provide the groundwork to define changes occurring with esophagitis. b) We will determine how LES resting tone and esophageal and LES contraction in response to agonists are affected by induction of experimental esophagitis in the cat. We will confirm that in esophagitis the mechanisms responsible for storage and release of intracellular Ca++ are affected, but those regulating influx of extracellular Ca++ are not, and we will investigate changes in the cycling of inositol phospholipids, which are thought to be responsible for release of intracellular Ca++ stores. These data will define changes in calcium handling mechanisms, and in cycling of inositol phospholipids associated with esophagitis, will clarify the relationship between LES and esophageal function and acid induced damage, and may provide a rationale for its prevention.
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