Benzimidazolones enhance the function of epithelial Na+ transport |
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Authors: | M Laube SU Kimpel P Dietl UH Thome OH Wittekindt |
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Affiliation: | 1.Division of Neonatology, University of Leipzig, Leipzig, Germany;2.Department of Pediatrics, University of Ulm, Ulm, Germany;3.Department of General Physiology, University of Ulm, Ulm, Germany |
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Abstract: | Background and PurposePharmacological 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 ApproachEffects on vectorial Na+ transport and amiloride-sensitive apical membrane Na+ permeability were determined by measuring short-circuit currents (ISC) 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 ResultsISC 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 ISC. 5-(N-Ethyl-N-isopropyl)amiloride-induced inhibition of ISC was not affected. The benzamil-sensitive ISC was increased in benzimidazolone-stimulated monolayers. Pretreating the apical membrane with amiloride, which inhibits ENaC, completely prevented the stimulating effects of benzimidazolones on ISC. 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 ImplicationsBenzimidazolones 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. |
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Keywords: | ussing chamber short-circuit current epithelial sodium transport patch clamp E-BIO |
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