Transport interactions of different organic cations during their excretion by the intact rat kidney

Transport interactions of different organic cations during their excretion by the intact rat kidney. Organic cations, in addition to being filtrated, are secreted or reabsorbed in the proximal renal tubule whereby they have to pass the contraluminal and the luminal cell membrane. Interactions with the transport of other organic cations can occur at either cell side, leading to inhibition or stimulation of net secretion or net reabsorption. A qualitative evaluation of such processes is possible by using the in vivo bolus injection of an organic cation as test substance. Measuring its urinary excretion profile in relation to that of inulin, under control conditions and after application of interfering organic cations, in combination with simultaneous registration of its tissue concentration, allows the demonstration of interaction and also the tentative identification of the cell side at which interference has taken place. As test substance the fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (4-Di-1-ASP⊕; ⊕ denotes permanent positively-charged organic cations was used, having a protein binding of 47% under the given experimental conditions. As interfering organic cations amiloride, benzylamiloride, choline⊕, cimetidine, and 2-methyl-4-(heptafluorobutoxy)-N-methylpyridinium⊕ were injected. It was found that: (1) 4-Di-1-ASP⊕ is filtered and net reabsorbed under control conditions (fractional excretion 0.54 ± 0.1). All net secreted interfering substances, except bidirectional transported choline⊕, injected simultaneously with 4-Di-1-ASP⊕, showed an interference with renal excretion of net reabsorbed 4-Di-1-ASP⊕, by (2) instantaneously increasing its reabsorption, resulting in a 28 to 33% decrease in urinary excretion, and (3) augmenting its tissue concentration by 19 to 58%. (4) A prolonged effect of the interfering substrates could be observed after a third injection of 4-Di-1-ASP⊕ (without inhibitor) showing an increased tissue concentration of 4-Di-1-ASP⊕ of 36 to 46%. The complex interfering pattern of the applied organic cations can be explained by a trans-stimulation of 4-Di-1-ASP⊕ net reabsorption at the luminal cell side, leading to an increased intracellular content of 4-Di-1-ASP⊕.