Interaction of thiazide and loop diuretics with the basolateral para-aminohippurate transport system in isolated S2 segments of rabbit kidney proximal tubules.
The effect of thiazide and loop diuretics on the tubular uptake of [3H]para-aminohippurate ([3H]PAH), a marker of the organic anion transport system, was tested in vitro on single S2 segments of the proximal tubule of rabbit kidneys. Because the tubules were not perfused, and hence were collapsed, the tubular [3H] PAH uptake reflects [3H]PAH transport across the contraluminal membrane. The diuretics were added to the bath solution in at least six different concentrations. The concentration of [3H]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-maximum PAH uptake. The results show that all of the nine diuretics tested inhibited [3H]PAH uptake. The IC50 values of the individual drugs ranged from 3 to 400 mumol/l. In general, thiazide diuretics had a lower affinity to the PAH transporter than loop diuretics. This probably results from differences in the pKa values which range from 3.6 to 4.1 for the loop diuretics and from 9.2 to 10 for the thiazide diuretics. 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 [3H]PAH uptake which may indicate a positive cooperative interaction of these 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 identical.(ABSTRACT TRUNCATED AT 250 WORDS)
Bartel
C
C
Department of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen, Federal Republic of Germany.
Wirtz
C
C
Brändle
E
E
Greven
J
J
D000818:Animals; D001581:Benzothiadiazines; D001692:Biological Transport / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D011817:Rabbits; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics*
D001581:Benzothiadiazines; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D010130:p-Aminohippuric Acid