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.