CHEMICAL HYPOXIA INCREASES JUNCTIONAL PERMEABILITY AND ACTIVATES ELECTROGENIC ION-TRANSPORT IN HUMAN INTESTINAL EPITHELIAL MONOLAYERS

Background. The intestinal epithelial tight junction restricts the par acellular permeation of ions and nonelectrolytes. We hypothesized that this function could be altered or disrupted during cellular adenosine triphosphate (ATP) depletion (chemical hypoxia). Methods. T84 monolay ers grown on permeable supports were studied by electrophysiologic and flux techniques. Mitochondrial and glycolytic inhibitors were used to deplete cellular ATP. Results. Transepithelial resistance to passive ion flow (R) rapidly decreased to 36% of control values with chemical hypoxia, an effect that was reversible if control conditions were rest ored within 1 hour. As ATP levels declined, a transient Cl- secretory current developed but disappeared as ATP levels reached 5% of control values. Both the secretory current and fall in R were abolished when a mbient Cl- was replaced with gluconate but not with Br- or NO3-, or wh en N-methylglucamine replaced Na+. Transepithelial flux of mannitol bu t not insulin was increased during ATP depletion. Dual Na+-mannitol fl ux analysis confirmed that the decrease in R was due to an increase in paracellular, not transcellular, permeability. Dilution potentials in dicated altered charge selectivity of the junctional pathway. Conclusi ons. Chemical hypoxia in intestinal epithelial monolayers alters but d oes not disrupt the