S3226, A NOVEL INHIBITOR OF NA+ H+ EXCHANGER SUBTYPE 3 IN VARIOUS CELL-TYPES/

Inhibition of Na+/H+ exchange (NHE) subtypes has been investigated in a study of the mouse fibroblast L cell line (LAP1) transfected with hu man (h) NHE1, rabbit (rb) NHE2, rat (rt) or human (h) NHE3 as well as an opossum kidney cell line (OK) and porcine renal brush-border membra ne vesicles (BBMV). S3226 ethyl-phenyl]-N-isopropylidene-2-methyl-acry lamide dihydrochloride} was the most potent and specific NHE3 inhibito r with an IC50 value of 0.02 mu mol/l for the human isoform, whereas i ts IC50 value for hNHE1 and rbNHE2 was 3.6 and congruent to 80 mu mol/ l, respectively. In contrast, amiloride is a weak NHE3 inhibitor (IC50 >100 mu mol/l) with a higher affinity to hNHE1 and rbNHE2. Cariporide (4-isopropyl-3-methylsulphonyl-benzoyl-guanidine methane-sulphonate), which has an IC50 for NHE3 of approximately 1 mmol/l, is a highly sele ctive NHE1 inhibitor (0.08 mu mol/l). Therefore, S3226 is a novel tool with which to investigate the physiological and pathophysiological ro les of NHE3 in animal models.