Summary
Using the modified Sperber technique in the hen the relationship between renal tubular secretion and urinary excretion of electrolytes of three alkaline diuretics was studied. The true tubular excetion fraction (TTEF) averaged 0.39, 0.60 and 0.01, respectively for amiloride, tizolemide and MK-447. Thus, there was extensive active tubular secretion of amiloride and especially of tizolemide, while a tubular secretion of MK-447 could not be established. The TTEF values of amiloride and tizolemide were significantly reduced by coadministration of mepiperphenidol (Darstine), an inhibitor of organic cation transport while these values were unaffected by the organic anion transport inhibitor novobiocin. Thus, amiloride and tizolemide are transferred from peritubular blood to the urine by an organic cation transport system, thereby significantly increasing the intraluminal concentration of the respective diuretic. This contributed significantly to the urinary electrolyte effects of each drug (in the case of amiloride a natriuretic and potassium-sparing effect and for tizolemide mainly a saluretic effect) since these effects were elcited predominantly on the ipsilateral side after renal portal infusion of the diuretic on one side and coinfusion of Darstine significantly reduced these excess excretions. Assuming a distal site of action, it seems therefore that a significant part of the renal electrolyte effects of amiloride (tizolemide) are coupled to its active tubular secretion and evoked from the luminal (urine) side of the avian nephron. In further support of a direct action of these diuretics on tubular cells, the renal clearances of 51-Cr-EDTA and 125-I-Na-o-iodohippurate were symmetrical during unilaterallity in electrolyte excretions. There was a small but significant ipsilateral excess saluresis after portal infusion of MK-447 that was not reduced by Darstine. This might be related to the higher concentrations of MK-447 in peritubular blood on the side of the infusion. It is suggested that MK-447 reaches its site(s) of action primarely by passive diffussion from the peritubular side of the nephron.
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Odlind, B. Renal tubular secretion and effects of the alkaline diuretics amiloride, tizolemide (Hoe 740) and 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK-447). Naunyn-Schmiedeberg's Arch. Pharmacol. 317, 357–363 (1981). https://doi.org/10.1007/BF00501319
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DOI: https://doi.org/10.1007/BF00501319