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Background  Loop diuretics are highly natriuretic but their short duration of action permits postdiuretic sodium retention, which limits salt loss unless dietary salt is severely restricted. We tested the hypothesis that a more prolonged duration of action would enhance salt loss.    Methods and Results  Ten healthy participants were crossed over between 20 mg of oral immediate‐release or extended‐release ( ER ) torsemide while consuming a fixed diet with 300 mmol·d −1  of Na + . Compared with immediate‐release, plasma torsemide after  ER  was 59% lower at 1 to 3 hours but 97% higher at 8 to 10 hours as a result of a >3‐fold prolongation of time to maximal plasma concentrations. The relationship of natriuresis to log torsemide excretion showed marked hysteresis, but participants spent twice as long with effective concentrations of torsemide after  ER , thereby enhancing diuretic efficiency. Compared with immediate‐release,  ER  torsemide did not reduce creatinine clearance and increased fluid (1634±385 versus 728±445 mL,  P <0.02) and Na +  output (98±15 versus 42±17 mmol,  P <0.05) despite an 18% reduction in exposure. Neither formulation increased K +  excretion.    Conclusions  Torsemide  ER  prolongs urine drug levels, thereby increasing the time spent with effective drug concentrations, reduces postdiuretic Na +  retention, and moderates a fall in glomerular filtration rate. It caused significant Na +  loss even during very high salt intake. Thus, a short duration of action limits salt loss with loop diuretics. These conclusions warrant testing in subjects with edema and heart failure.

Sodium and Fluid Excretion With Torsemide in Healthy Subjects is Limited by the Short Duration of Diuretic Action