MODULATION OF THE TIGHT JUNCTIONS OF THE CACO-2 CELL MONOLAYERS BY H-2-ANTAGONISTS

Purpose. The tight junctions in the intestinal epithelium represent hi ghly specialized intercellular junctions. Ranitidine, an H-2-antagonis t, causes a tightening of the tight junctions. Hence, we have investig ated the effect of ranitidine and other H-2-antagonists on the functio n of the intestinal tight junctions. Methods. Effect of the H-2-antago nists on the tight junctions has been investigated using the transepit helial electrical resistance (TEER) and the transport of mannitol acro ss the Caco-2 cell monolayers. Results. Four different H-2-antagonists caused an increase in the TEER across the Caco-2 cell monolayers, acc ompanied by a decrease in the permeability for mannitol. The effect wa s concentration-dependent and saturable. Ranitidine and famotidine, ca used a decrease in their own transport rate across the Caco-2 cells. R anitidine competitively inhibited the increase in TEER caused by famot idine, whereas compounds which represent molecular fragments of raniti dine had no effect The relative potency of the four H-2-antagonists in causing an increase in the TEER correlated inversely with the oral bi oavailability of these compounds in humans. Conclusions. We hypothesiz e that the H-2-antagonists exert their effect on the tight junctions o f Caco-2 cells by modulation of interactions among proteins associated with the tight junctional complex.