The diuretic effect of muzolimine

Abstract

Muzolimine produces a diuresis in the loop of Henle. Unlike other diuretics of this kind, the effect of muzolimine is slow and its action is long lasting. The present study was designed to examine the mechanism of action of muzolimine in isolated in vitro perfused rabbit cortical thick ascending limb segments (cTAL). In a first series it was confirmed that muzolimine itself in a concentration of up to 10⁻⁴ mol/l had no effect on the equivalent short circuit current (Isc), corresponding to the rate of active NaCl reabsorption, in cTAL segments neither from the lumen nor from the bath side. In a second series of experiments, muzolimine was administered intravenously (70 μmol/kg) to male Wistar rats, and the clearances of inulin, Na⁺ and K⁺ were calculated. Muzolimine, after a lag phase of 5 to 20 min caused a marked diuresis and natriuresis, but had only a minor effect on glomerular filtration rate and on K⁺ excretion. The urines of these animals were diluted with isotonic saline, and were examined in rabbit cTAL segments for their ability to block Isc. It was found that the urines of the antidiuretic period were devoid of effects, whereas the diuretic urines inhibited Isc strongly down to a dilution of 300 times when they were perfused in the lumen. The same diluted urines had no effect from the bath side. In a third series, probenecid (100 μmol/kg) was administered i.v. to rats undergoing a muzolimine induced saluresis. It was found that probenecid inhibited the diuresis and saluresis. The present data indicate (i) that muzolimine itself has no diuretic potency, (ii) that the substance is metabolized in the intact animal and that a diuretic metabolite is generated, (iii) that this active metabolite is accumulated in tubule fluid by proximal secretion, and (iv) that it inhibits active NaCl transport in the cTAL segment from the lumen side.