Tubular Effects of the Diuretic Torasemide

Abstract

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 natriure-sis 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 µmol/l; active transport was measured as the equivalent short-circuit current. Half-maximal inhibition by torasemide was observed with 0.1 µmol/ 1 at pH 8.0 and with 3.7 µmol/l at pH 6.0, indicating that the unprotonated form of torasemide is biologically active and that changes in luminal pH have a profound effect on its concentration-response curve.

Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters

“…We confirmed that torsemide interacts with the human OATs 1, 3 and 4 in vitro as was expected from an earlier clinical study and in vitro studies with other loop diuretics [11,12]. We observed a 6.6-fold interindividual variation in the renal clearance of torsemide, compared with about a twofold difference in creatinine clearance.…”

“…Torsemide is a loop diuretic that is eliminated renally with a clearance of the unbound fraction (1–2%) of about 1200 ml min −1 [8]. Thus, torsemide is thought to be eliminated primarily via active anion secretion, and that its active excretion accounts for about 90% of torsemide renal clearance [8, 12]. However, the interaction of torsemide with the OATs has not been investigated.…”

Torasemide is an effective diuretic in the newborn rabbit

“…Its mode of action, pharmacokinetics, and pharmacodynamics have been reported in a variety of clinical situations [8][9][10][11][12].…”