On the Mechanism of Acute Tolerance to Furosemide Diuresis

Abstract

The renal response to continuous furosemide infusion (8 mg/h) and subsequent ECV changes was studied in 8 healthy volunteers. Furosemide increased urine flow from a basal flow of 4.3 ml/min to a maximum of 15.4 ml/min. During dehydration (-1.8 kg) the diuresis decreased to 8.4 ml/min. The sodium, chloride and potassium excretion likewise decreased. This reduction in diuretic effect (acute tolerance) was accompanied by significantly increased plasma levels of norepinephrine (1.38 to 2.14 nmol/l), PRA (0.52 to 1.13 ng/ml/h) and aldosterone (0.29 to 0.45 nmol/l). After rehydration the urine flow increased to 23.1 ml/min. The changes in diuretic response from initial effect to the dehydrated state and after rehydration were mainly a consequence of changed renal sensitivity to furosemide (urinary excretion of 21 to 14 to 35 µmol Na⁺ per µg furosemide excreted). It is proposed that activation of the sympatheti nervous system and/or the renin-angiotensin-aldosterone system may play a role in mediating the acute tolerance to furosemide diuresis. The relative importance of each remains to be clarified.

Key words:

• Loop diuretic
• Furosemide
• Tolerance
• Dehydration
• Pharmacokinetics
• Pharmacodynamics
• Sympathetic nervous system
• Renin-angiotensin-aldosterone system
• AVP