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Abstract
Most of the electrical potential-driven 22Na+ uptake in toad bladder membrane vesicles can be blocked by the diuretic amiloride. Analysis of the amiloride inhibition curve indicates the presence of two pathways with low and high affinities to the diuretic (Garty, H. (1984) J. Membr. Biol. 82, 269-279). The selectivity of these pathways to amiloride was explored by comparing the inhibition curve of this diuretic with those of 10 of its structural analogues. The relative potencies of various amiloride-like compounds as blockers of the flux component with high affinity to amiloride were in good agreement with the structure-activity relationships elucidated from transepithelial short-circuit current measurements. Thus, this pathway is most probably the apical Na+-specific channel. The other pathway with lower affinity to the diuretic was relatively insensitive to modifications of the amiloride molecule, and the structure-activity relationships measured for the inhibition of this pathway were different from those reported for any other amiloride-blockable process. Other experiments have established that the Na+ flux with low affinity to amiloride is electrogenic and is not mediated by a Na+/H+ or Na+/Ca2+ exchanger, Na+-hexose cotransporter, or the Na+/K+-ATPase. The data indicate that tracer flux measurements in toad bladder membrane vesicles monitor, in addition to the well-characterized apical Na+ channels, another amiloride-blockable electrogenic Na+ transporter. This pathway could be responsible for the basolateral amiloride-blockable Na+ conductance recently observed in nystatin-treated bladders (Garty, H., Warncke, J., and Lindemann, B. (1987) J. Membr. Biol. 95, 91-103).
Highlights
From the $Department of Membrane Research, The Weizmann Institute of Science, Rehovot, 72100, Israel and TlMerck Sharp and Dohme Research Laboratories, West Point,Pennsylvania 19486
1982).On the other hand, tracer insensitive to modificationosf the amiloride molecule, fluxes measured in membrane vesicles derivedfrom toad and the structure-activity relationships measured for bladder (Garty, 1984),pig kidney (Barbry et al, 1986),and the inhibition of this pathway were different from bovine cortex (Kleyman et al, 1986) indicated the presence thosereportedfoar nyothear miloride-blockable of two Nap+athways wihtihgh
Na+-hexosecotransporter, or theNa+/K+-ATPase.The H’ or a Na+/Ca2+ exchanger (Garty,1984).In recent experidata indicate that tracer flux measurements in toad ments, “Na+ fluxes with low affinity to amiloride were obbladder membrane vesicles monitor, in addition ttohe served in membrane vesicles derived from several other pLlnlwooayierrntsiilhddtdl-aweeectm--ihabbnayall-ronotcacrncocekk,utaaeaBltbdrbe.illzdeb(eeee1dlbN9erla8caeap+t7sdrip)docJocaeg.nolreMssnnNidibea(cumlNG+ecbtaacaf+rrhnot.tayrcrHBane, nti.nho,serWelpel.soc9ba,er5raatnne,sntcrolo.ykTltaehht,oeei9Jbsrr1.asa,e-lmar1avni0m-ed3di)-.ippwutanilropgalesthssaceteadkanesapecpe.pesiat,Ishrttubweehbunlaeisttasltfyna(fluMnoueltxtllioyeairicnlenatfxrnhrtopahigbrceeeeitttsniaeosiabdecnlsd.((,eoduinn1rnpcli9yvte8ote,6hbno;yefcBbohv7rymiia0gdla%phignledKe)ostomoe+sefeyatgscbtrahisanloee.d),fntioe1caa9tnemna8todl7iifNl)noc.Caro’tia+mhdI2nee-+
Summary
Similar measurements were carried out using several conpresence of a membrane potential which amplifies the tracer centrations of each of the compounds listed in Table I and uptake through electrogenic pathways and prevents its equil- used to determine the maximal nondepolarizing concentration ibration within a few seconds (Garty et al, 1983b).Amiloride of each analogue.
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