STEREOSPECIFICITY IN CONTRALUMINAL AND LUMINAL TRANSPORTERS OF ORGANIC CATIONS IN THE RAT RENAL PROXIMAL TUBULE

The effect of chirality on the interaction of substrates with the orga nic cation transporters in the proximal tubule of rat kidney was inves tigated. The apparent K-i values of the enantiomers/ diastereomers of ephedrine and norephedrine and the stereoisomers of deprenyl, tranylcy promine, disopyramide, verapamil, pindolol and quinine/quinidine were determined against the contraluminal organic cation transporter, the l uminal H+/organic cation exchanger and the luminal choline(+) transpor ter, using the stop-flow luminal or contraluminal capillary microperfu sion method. The ephedrine/norephedrine enantiomers/diastereomers had apparent K-i values against the contraluminal organic cation transport er in the range of 0.8 to 2.4 mM, and only norpseudoephedrine showed s ignificant enantioselectivity. The same substrates had apparent K-i va lues against the luminal H+/organic cation exchanger between 3.0 and 1 5.0 mM, and ephedrine, norephedrine and norpseudoephedrine showed enan tioselectivity. The K-i values against the luminal choline(+) transpor ter were even higher (7.2-19.1 mM) and demonstrated no enantioselectiv ity. The verapamil and deprenyl enantiomers showed selectivity against the luminal choline(+) transporter, as did quinine and quinidine agai nst the contraluminal organic cation transporter. In all other instanc es enantioselectivity was not observed. In no case was the difference in the K-i values of the enantiomers/isomers greater than a factor of 3. The data confirm the high degree of nonspecificity of the renal org anic cation transporters. Evaluation of three-dimensional molecular mo dels of the ephedrine enantiomers/diastereomers suggests that the spat ial orientations of the amino group and, to a lesser extent, the OH gr oup and possibly the terminal CH3 group are of importance for differen t interactions with the transporters.