The effects of muzolimine and urine from muzolimine-treated rats on Na+K+Cl- cotransport in Madin-Darby canine kidney cells.
Muzolimine is a loop diuretic with an original chemical structure devoid of the acidic or sulfonamide group known to be necessary for an interaction with Na+K+Cl- cotransport. We studied the effects of urine from muzolimine-treated rats on the Na+K+Cl- cotransport-dependent 86Rb influx in MDCK cells. Na+K+Cl- cotransport was inhibited by urine obtained 15 min (42% inhibition) and 60 min (49% inhibition) after muzolimine injection (50 mumol/kg i.v.). Muzolimine itself was not detectable in the urine. Probenecid (100 mumol/kg i.v.) suppressed both the diuretic effect of muzolimine and the inhibition of Na+K+Cl- cotransport by urine from muzolimine-treated rats. These results suggest that the diuretic effect of muzolimine is due to the metabolism of muzolimine into an active compound which inhibits Na+K+Cl- cotransport after its secretion into the tubular lumen via a proximal pathway. The direct effect of muzolimine on Na+K+Cl- cotransport in MDCK cells was also tested: surprisingly, the inhibition of 86Rb influx was significant in the presence of muzolimine (IC50 = 1.44 microM). We show that this effect was due to the metabolism of muzolimine by these cells into an active compound.
Grima
M
M
Institut de Pharmacologie, Faculté de Médicine, Université Louis Pasteur, Strasbourg, France.
Michel
B
B
Barthelmebs
M
M
Stephan
D
D
Imbs
J L
JL
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D004285:Dogs; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009156:Muzolimine / Q000494:pharmacology* / Q000652:urine; D011188:Potassium / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012414:Rubidium Radioisotopes; D012964:Sodium / Q000378:metabolism*
D002712:Chlorides; D011506:Proteins; D012414:Rubidium Radioisotopes; D009156:Muzolimine; D012964:Sodium; D011339:Probenecid; D011188:Potassium