Tubular effects of the diuretic torasemide

Torasemide is a lipophilic loop diuretic which is largely metabolized in the liver and has an almost neutral pKa. Experiments were designed to address the questions of whether torasemide is secreted by the proximal tubule, and hence accumulates in tubular fluid, whether torasemide paralyses active transport in the cortical thick ascending limb of the nephron and hence reduces its ATP requirement, and finally whether torasemide is active in its protonated or unprotonated form. Intravenous torasemide, 10 mg/kg, induced a marked diuresis and natriuresis and a moderate kaliuresis in antidiuretic rats. All effects were dose-dependently suppressed by intravenous probenecid, 20-80 mg/kg, indicating that torasemide is secreted by the anion secretory system of the proximal tubule. A time-dependent depolarization of the basolateral membrane of in vitro perfused rabbit cortical thick ascending limb segments was observed after removal of metabolic substrates and after addition of ouabain. This effect, caused by Na+ entry, K+ loss and cell swelling, was prevented when torasemide was added to the luminal perfusate before substrate removal or addition of ouabain, indicating that torasemide significantly reduced ATP consumption of the cortical thick ascending limb. To test whether protonated or unprotonated torasemide was the biologically active compound, cortical thick ascending limb segments were perfused over the pH range 6-8 and torasemide was added in the concentration range 0.01-10 mumol/l; active transport was measured as the equivalent short-circuit current.(ABSTRACT TRUNCATED AT 250 WORDS)