1,1'-DIETHYL-2,2'-CYANINE (DECYNIUM22) POTENTLY INHIBITS THE RENAL TRANSPORT OF ORGANIC CATIONS

The excretion of cationic compounds by renal proximal tubule cells inv olves at least two distinct transporters: the basolateral type which t ransports organic cations from the plasma into the proximal tubule cel l, and the apical type which secretes the organic cations into the lum en of the tubule. However, potent inhibitors were known for neither ty pe of transporter. Here we introduce a compound, decynium22, that pote ntly, competitively, and selectively inhibits the apical type of the r enal organic cation transporter. The transport of the prototypical org anic cation C-14-tetraethylammonium through the apical plasma membrane of clonal proximal tubule cells (LLC-PK1) was used as experimental sy stem. Initial rates of C-14-tetraethylammonium transport into LLC-PK1 cells were saturable, the K(m) and V(max) being 27 mumol/l and 200 pmo l/(mg protein . min), respectively. Decynium 22 competitively and pote ntly inhibited C-14-tetraethylammonium transport (K(i) = 5.6 nmol/1). Moreover, the effect of decynium 22 on basolateral to apical directed transepithelial transport of C-14-tetraethylammonium through a conflue nt monolayer of LLC-PK1 cells was determined. Decynium 22 (30 nmol/1) applied to the apical medium, reduced transepithelial transport by 760 %and increased intracellular accumulation of C-14-tetraethylammonium 1 .5-fold. In contrast, application of 30 nmol/l decynium22 to the basol ateral medium failed to affect transepithelial transport and intracell ular accumulation of C-14-tetraethylammonium. Decynium22 is the most p otent inhibitor of the renal transport of organic cations known so far . With decynium22 it is now possible to distinguish precisely between a decynium22-sensitive apical type and a decynium22-resistant basolate ral type of renal organic cation transporter in renal proximal tubule cells.