ALDOSTERONE INDUCED COLONIC H+ SECRETION & VESICLES

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This investigator has previously demonstrated that colonic sodium chloride absorption is markedly altered by aldosterone or dexamethasone. This was accompanied by the appearance of new luminal membrane vesicles in colon from aldosterone but not from dexamethasone treated rats. The aldosterone induced vesicles are similar in appearance and location to vesicles thought to be involved in H+ secretion in turtle urinary bladder, in the intercalated cell of rat medullary collecting duct, and possibly in the gastric parietal cell. Preliminary pH stat experiments indicate that rat distal colon secretes H+, that H+ secretion exceeds lactate production, that H+ secretion has both sodium-dependent and sodium-independent components, and that maneuvers known to produce intracellular acidification stimulate H+ secretion. In parallel with these studies, morphologic studies demonstrate a reduction in vesicle number and migration toward the lumen after intracellular acidification produced by CO2 exposure consistent with the possibility of fusion of vesicle membrane and addition of H+ pumps to the apical membrane. Experiments with acridine orange have shown that there are acidic vesicles in rat colon. Thus, it is possible that aldosterone activates a new form of H+ secretion in the rat distal colon, one involving membrane vesicles and exocytotic fusion. This investigator plans to further characterize H+ secretion in distal colon segments from untreated rats and from rats treated with aldosterone or dexamethasone. This will be accomplished by ion substitution studies and by the use of specific inhibitors. In parallel with these studies, quantitative morphometry and fluorescent probes will be utilized to determine the distribution of aldosterone induced acidic vesicles and to examine the response to agents which augment or inhibit H+ secretion. The specific long-term objectives are to study the induction of this system by aldosterone, its regulation once it is in place, and the role of the cytoskeleton in its regulation. These studies are important for several reasons. Neither H+ secretion nor ion transport regulated by exocytotic fusion have been demonstrated in intestinal epithelia. Examination of the function of these aldosterone induced membrane vesicles is likely to provide new information in this regard. These studies are highly relevant to our understanding of intestinal ion transport and the modification thereof by mineralocorticoid and glucorticoid steroids.