Indomethacin secretion in the isolated perfused proximal straight rabbit tubule. Evidence for two parallel transport mechanisms.

Abstract

We studied indomethacin as a probe of anion transport across the isolated perfused proximal straight tubule of the rabbit and discovered that a substantial component of transport may occur by anion exchange at the basolateral membrane. Various perturbations involving direct or indirect dissipation of the cellular sodium gradient (ouabain, sodium-or potassium-free solutions, cooling to 18°C) resulted in only a 50% inhibition of indomethacin transport, which raised the question of a co-existent alternative pathway for secretion. Similarly, the anion exchange inhibitor, 4,4'-diisothiocyanostilbene (DIDS), diminished indomethacin secretion by only 50%. Cooling followed by DIDS or the reverse sequence resulted in additive inhibition such that the combination abolished active secretion of indomethacin.We conclude that active secretion of indomethacin by the proximal straight tubule appears to be in part sodium gradient dependent; the remainder may be driven by an anion exchanger on the basolateral membrane.

Indometacin: Renal Handling and Effects in the Isolated Perfused Rat Kidney

“…More than one trans porter is involved in the active secretion. Part of the secretion occurs by a sodiumcoupled anion transporter and another part occurs by an anion exchanger [11], Trans port from the cells to the lumen, across the brush-border membrane, occurs probably by facilitated diffusion [12]. As a consequence of these transport processes, indometacin might accumulate in the cells.…”

“…Indometacin is a weak organic acid and its renal handling involves glomer ular filtration, passive reabsorption and ac tive secretion. It is secreted actively at the basolateral membrane, partly by a sodiumcoupled anion transport process and partly by an anion exchanger [11], At the brushborder membrane transport occurs probably by facilitated diffusion [12], Active transport across the basolateral membrane and passive transport across the brush-border membrane might lead to accumulation in the proximal tubular cells. Accumulation of indometacin has been observed using autoradiographic methods [13,14].…”