Adrenergic agonists, acting through a specific Alpha2-receptor, have been shown to affect ileal ion transport in vitro. However, little is known about the intracellular events mediating this process or its regulatory role in the intact animal. These questions are key to understanding and developing new therapeutic approaches to diseases in which watery diarrhea may be a consequence of altered noradrenergic innervation of the intestinal mucosa. The present study proposes to (1) investigate the intracellular events that mediate Alpha2-adrenergic response in ileal mucosa, specifically adenylate cyclase and intracellular free calcium. A technique, using a calcium-selective, pH insensitive, fluorescent probe has been proposed to study changes in intracellular free calcium concentrations in both the intact tissue and isolated enterocytes; (2) Evaluate in the intact animal the role of noradrenergic innervation of the epithelium in the homeostatic regulation of intestinal water and electrolyte transport. Methods for measuring the extent of functionally relevant innervation will be established; and (3) Study two clinical entities, diabetic diarrhea and opiate withdrawal diarrhea, where there is reason to believe that the impaired noradrenergic innervation of the epithelium results in a secretory (or anti-absorptive) diarrhes. The methods proposed in (2) will be used to study this hypothesis in established animal models.
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