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The effects of the Na+-channel-blocking diuretic agent amiloride were assessed in the rabbit gall-bladder epithelium, a low-resistance epithelium with an isosmotic, coupled NaCl transport mechanism. Amiloride caused a rapid, reversible, and dose-dependent decrease in fluid absorption when applied from the mucosal side in concentrations between 8.8 X 10(-5) and 1.76 X 10(-3) M. These concentrations were without effect from the serosal side, suggesting an action of amiloride in the luminal cell membrane as in high-resistance epithelia. Amiloride did not affect the epithelial resistance or the passive serosa-to-mucosa Na+ flux, while net Na+ and water reabsorption were inhibited in parallel. Thus, amiloride did not affect the paracellular tight junction pathway, but inhibited a transcellular, coupled salt and water transport mechanism. The kinetics of the amiloride effect were of a Michaelis-Menten type. The dose of amiloride giving 50% inhibition of fluid absorption (ID50) was 4 X 10(-4) M, a value about three orders of magnitude higher than in high-resistance, Na+-retaining epithelia. The percentage inhibitory effect at each concentration of amiloride increased with increasing rate of spontaneous (control) fluid transport, reaching maximal responses fitting a Michaelis-Menten kinetic with an ID50 of 1.5 X 10(-4) M. No effects of changing the extracellular Na+ concentration between 51 and 145 mequiv/l on the maximal inhibitory effect of amiloride on Na+ and water reabsorption were observed. This suggests a non-competitive type of action of amiloride on a Na+-dependent isosmotic fluid transport mechanism. Removal of mucosal Ca2+ did not alter the effect of amiloride. The implications of these findings are discussed in relation to concepts concerning the mechanism of isosmotic salt and water transport. The data are compatible with the concept that amiloride interferes with a Na+-dependent formation and transcellular transport of isosmotic fluid volumes in a sequestered compartment in the epithelial cells.