INTERACTION OF DIPYRIDAMOLE, A NUCLEOSIDE TRANSPORT INHIBITOR, WITH THE RENAL TRANSPORT OF ORGANIC CATIONS BY LLCPK1 CELLS

Dipyridamole is a well-known inhibitor of nucleoside transport by vari ous cell membranes and is frequently used in in vitro studies that cha racterize nucleoside transport properties. Because interactions betwee n the renal transport of organic cations and nucleosides have previous ly been suggested,we studied the effect of dipyridamole on the renal t ransport of the typical organic cations cimetidine and N-1-methylnicot inamide by LLCPK1 monolayer cells grown on a permeable support. [C-14] Mannitol was used to correct for extracellular flux. Basolateral to ap ical transcellular flux (transepithelial flux extracellular flux) of [ H-3]cimetidine was significantly reduced by the monolayer cells (90%) in the presence of 50 mu M dipyridamole. In addition, the effect of di pyridamole on cimetidine renal transport was dose dependent (IC50 = 7. 7 mu M). The dipyridamole inhibitory effect was nearly comparable with the effect of 1 mM quinine (a typical organic cation transport inhibi tor), which led to 95% inhibition of cimetidine renal transport over t ime. The dipyridamole effect on N-1-methylnicotinamide renal transport was less potent. The effect of 1 mM of typical probes of the nucleosi de transporters (i.e., thymidine, adenosine, uridine) and the effect o f 100 nM of another nucleoside transport inhibitor, dilazep, were also studied on cimetidine transport by LLCPK1 monolayer cells. These comp ounds did not exert any significant effect. These results suggest that dipyridamole, a widely used nucleoside transport inhibitor, is also a n inhibitor of organic cation renal transport and they alert us to pos sible interactions between the renal transport of nucleosides and orga nic cations. This finding also has relevance to the interpretation of in vitro studies using this agent as a nucleoside membrane transport i nhibitor.