The major thrust of the proposed work will be to identify both a cellular and at more macroscopic levels, the mechanisms of protection of the surface and other epithelial cells of the stomach and duodenum against a hostile luminal environment. Using new information and new techniques, the investigations will be directed toward the following questions: 1) What are the mechanisms by which intracellular acid-base balance is regulated in the normal gastric and duodenal mucosae, with particular reference to proposed basolateral Na+/H+ and Cl-/OH- (HCO3 -) exchangers? How are these mechanisms perturbed by physiologic changes such as stimulation or inhibition of acid secretion, and by physiologic conditions which predispose to ulceration? 2) Do injurious agents such as aspirin (ASA), salicylate (SA), other non- steroidal anti-inflammatory agents, and drugs such as prostaglandins on growth factors such as EGF affect intracellular acid-base balance, and if so, how? 3) What are the mechanisms by which ASA and other non-steroidal anti-inflammatory agents affect and damage the gastric mucosa? These studies pursue some promising leading uncovered in our previous experiments. The intracellular pH measurements will be made in isolated sheets of intact mucosa, rabbit gastric glands, and in isolated surface and/or oxyntic cells using an intracellular fluorescent dye, BCECF, whose accuracy and reliability in these models have been well validated by us and by others. By manipulating the pH, pCO2 and electrolyte composition of the bathing medium, the regulation of the intracellular pH by various mechanisms such as HCO-/Cl- or Na+/H+ exchangers can be elucidated. In addition, the effects of drugs such as aspirin and other non-steroidal anti-inflammatory agents on intracellular pH will be examined. Since much of our previous data indicates that the effects of aspirin and other non- steroidal anti-inflammatory drugs are primarily exerted on the vasculature and/or platelets, we propose to study the action of these drugs using permeability of Evan's blue, staining with monastral blue, and injection of the microvasculature with a modified silicone rubber. We also wish to pursue previous preliminary data suggesting that prostaglandins inhibit the conversion of ASA to SA by measuring the partition between ASA and SA in the blood of rats given I.V. ASA. The effects of inhibiting platelet aggregation with persantin on the lesions induced by I.V. ASA in rats should shed some further light on the mechamism of gastric injury by inhibitors of cyclo-oxygenase.
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