Regulation of Chloride Secretion in Mammalian Colon* A. W. Baird Department of Pharmacology, University College Dublin, Dublin 4. Abstract A number of procedures or interventions which activate electrogenic ion transport in mammalian intestine are reviewed. Using in vitro models it is possible to demonstrate direct or indirect pathways to stimulate chloride secretion. Such activation, in vivo, would change the gut from a state of net water absorption to one of fluid secretion. The movement of water is driven by electrical and osmotic gradients set up as a consequence of opening regulated ion channels in epithelial cells. Secretagogues may govern epithelial intraceUniar second messenger pathways to regulate ion channel activity directly or by activation of membrane bound receptors on the surface of epithelial cells. In health or disease secretagogues may be derived from cells within the attendant lamina propria of the intestinal mucosa. Pharmacological techniques may he employed to determine which mediators contribute to indirect stimulation of electrogenic ion transport by activation of neurons or of immunocytes (mast cells or phagocytes). Dissection and reconstruction of models of intestinal hypersensitivity reactions show that neuro-immune networks which regulate intestinal ion transport appear to be complex, functionally integrated systems. Analysis of such interactions may identify cellular or humoral targets with which to examine novel diagnostic, preventative or therapeutic strategies with regard to intestinal diseases. Virtually all external and internal surfaces of the human body are lined by a layer of cells - the epithelium. Epithelial monolayers are heterogeneous, comprising about 60% of the 200 characterised cell types. An epithelium is typically a continuous sheet of polarised cells associated with one another by specialised junctional domains. This layer forms a physical border between different biological environ- ments. Indeed, through selective processes of absorption and secretion, the epithelium actively contributes to homeostatic mechanisms which maintain inter- compartmental differences. The main function of the large intestine is conservation of water and ions. In addition, since the intestine is exposed to an enormous number of antigens including food, multicellular parasites, resident bacteria and viruses it acts as a containing barrier to limit otherwise excessive or inappropriate exposure of vital organs to potentially harmful stimuli. Distal intestine can be rap- idly and drastically converted from a water absorbing to a net secreting tissue. This is in itself a remarkable feature with, to take the example of cholera, consequences ranging from host protection (removal of the pathogen by a flushing mechanism) to host fatality. Diarrhoeal disorders may reflect one or more of a number of changes in epithelial function which alter the gut from an absorptive to a secretory organ(~. Fluid secretion results from a coordinated reduction in absorptive processes and generation of a net secretion of electrolytes which results in an osmotic gradient for water movement into the lumen. In the intestine absorptive and secretory functions are spatially separated. Absorption occurs across the villous and surface epithelial ceils whereas crypts are the site of secretory epithelial cells~2~.The osmotic pressures which underlie net fluid secretion in the gut result from the active *Conway Review Lecture 1993 secretion of two principal anions, chloride and bicarbonate, and of potassium~ Perhaps the most important of these processes and certainly that which has been most studied, is the electrogenic chloride movement through regulated chloride channels sited in the apical membrane of epithelial cells in colon and small intestine. These chloride channels which are chronically active in secretory diarrhoea were the first epithelial ion channel for which the primary structure was determined through the discovery of the CFTR gene~3L Extensive studies on regulation of chloride secretion have been made possible through identification of CFTR and also by studies of ion transport in human epithelial cell lines such as T84 which retain the phenotype of secretory cells of colonic origin. Cellular mechanisms for active chloride secretion with particular regard to intracellular second messenger systems have been reviewed elsewheret4,~l. Both calcium and cyclic AMP stimulate chloride secretion in isolated colonic secretory cells and in native epithelia. There appears to be functional synergism between secretagogues which increase intracellular free calcium and those which stimulate adenylate cyelase in T84 cells~6). A third intracellular second messenger system, cyclic GMP, is another mediator of intestinal chloride secretion which may be produced in response to heat stable E. coli enterotoxin ~ or to the endogenous intestinal peptide guanylintg). The use of single cell type, simple monolayer cultures of epithelial cells for biological studies is attractive and useful. However, such an approach is, in isolation, inad- equate for analysis and understanding of normal tissue function which in vivo reflects all possible interactions of structural components. Integrated physiology is, in the gastrointestinal tract as elsewhere, a reflection of dynami- cally interactive cellular communication networks. In ad- dition to a normally intact epithelium, the mammalian gut 277