Benzimidazolones enhance the function of epithelial Na? transport.

British journal of pharmacology

PubMedID: 23083067

Laube M, Kimpel SU, Dietl P, Thome UH, Wittekindt OH. Benzimidazolones enhance the function of epithelial Na? transport. Br J Pharmacol. 2013;168(6):1329-40.
BACKGROUND AND PURPOSE
Pharmacological enhancement of vectorial Na? transport may be useful to increase alveolar fluid clearance. Herein, we investigated the influence of the benzimidazolones 1-ethyl-1,3-dihydro-2-benzimidazolone (1-EBIO), 5,6-dichloro-1-EBIO (DC-EBIO) and chlorzoxazone on vectorial epithelial Na? transport.

EXPERIMENTAL APPROACH
Effects on vectorial Na? transport and amiloride-sensitive apical membrane Na? permeability were determined by measuring short-circuit currents (I(SC)) in rat fetal distal lung epithelial (FDLE) monolayers. Furthermore, amiloride-sensitive membrane conductance and the open probability of epithelial Na? channels (ENaC) were determined by patch clamp experiments using A549 cells.

KEY RESULTS
I(SC) was increased by approximately 50% after addition of 1-EBIO, DC-EBIO and chlorzoxazone. With permeabilized basolateral membranes in the presence of a 145:5 apical to basolateral Na? gradient, the benzimidazolones markedly increased amiloride-sensitive I(SC). 5-(N-Ethyl-N-isopropyl)amiloride-induced inhibition of I(SC) was not affected. The benzamil-sensitive I(SC) was increased in benzimidazolone-stimulated monolayers. Pretreating the apical membrane with amiloride, which inhibits ENaC, completely prevented the stimulating effects of benzimidazolones on I(SC). Furthermore, 1-EBIO (1 mM) and DC-EBIO (0.1 mM) significantly increased (threefold) the open probability of ENaC without influencing current amplitude. Whole cell measurements showed that DC-EBIO (0.1 mM) induced an amiloride-sensitive increase in membrane conductance.

CONCLUSION AND IMPLICATIONS
Benzimidazolones have a stimulating effect on vectorial Na? transport. The antagonist sensitivity of this effect suggests the benzimidazolones elicit this action by activating the highly selective ENaC currents. Thus, the results demonstrate a possible new strategy for directly enhancing epithelial Na? transport.