INTERACTION OF THIAZIDE AND LOOP DIURETICS WITH THE BASOLATERAL PARA-AMINOHIPPURATE TRANSPORT-SYSTEM IN ISOLATED S-2 SEGMENTS OF RABBIT KIDNEY PROXIMAL TUBULES

The effect of thiazide and loop diuretics on the tubular uptake of [3 H]para-aminohippurate ([H-3]PAH), a marker of the organic anion transp ort system, was tested in vitro on single S2 segments of the proximal tubule of rabbit kidneys. Because the tubules were not perfused, and h ence were collapsed, the tubular [H-3] PAH uptake reflects [H-3]PAH tr ansport across the contraluminal membrane. The diuretics were added to the bath solution in at least six different concentrations. The conce ntration of [H-3]PAH in the bath solution amounted to 1.3 mumol/l, and was 12 times lower than the PAH concentration (16 mumol/l) at half-ma ximum PAH uptake. The results show that all of the nine diuretics test ed inhibited [H-3]PAH uptake. The IC50 values of the individual drugs ranged from 3 to 400 mumol/l. In general, thiazide diuretics had a low er affinity to the PAH transporter than loop diuretics. This probably results from differences in the pK(a) values which range from 3.6 to 4 .1 for the loop diuretics and from 9.2 to 10 for the thiazide diuretic s. Furthermore, there was a highly significant dependence of affinity on the hydrophobic properties of the diuretics. At concentrations 10- to 100-fold lower than the IC50 values all diuretics stimulated [H-3]P AH uptake which may indicate a positive cooperative interaction of the se drugs with the PAH transporter. Within the group of loop diuretics the order of the affinity to the PAH transporter and to the Na, 2 Cl, K cotransporter in the thick ascending limb of Henle's loop was identi cal. It is concluded that hydrophobic properties and electrical charge of the diuretics are important parameters which determine their affin ity for the renal PAH transport system.