Modulation of the tight junctions of the Caco-2 cell monolayers by H2-antagonists

Purpose. The tight junctions in the intestinal epithelium represent highly specialized intercellular junctions. Ranitidine, an H-2-antagonist, causes a tightening of the tight junctions. Hence, we have investigated the effect of ranitidine and other H-2-antagonists on the function of the intestinal tight junctions. Methods. Effect of the H-2-antagonists on the tight junctions has been investigated using the transepithelial electrical resistance (TEER) and the transport of mannitol across the Caco-2 cell monolayers. Results. Four different H-2-antagonists caused an increase in the TEER across the Caco-2 cell monolayers, accompanied by a decrease in the permeability for mannitol. The effect was concentration-dependent and saturable. Ranitidine and famotidine, caused a decrease in their own transport rate across the Caco-2 cells. Ranitidine competitively inhibited the increase in TEER caused by famotidine, whereas compounds which represent molecular fragments of ranitidine had no effect The relative potency of the four H-2-antagonists in causing an increase in the TEER correlated inversely with the oral bioavailability of these compounds in humans. Conclusions. We hypothesize that the H-2-antagonists exert their effect on the tight junctions of Caco-2 cells by modulation of interactions among proteins associated with the tight junctional complex.