Development of acute tolerance to bumetanide: constant-rate infusion studies

Bumetanide was administered intravenously to four mongrel dogs as a bolus of 8.7 micrograms/kg, immediately followed by a constant-rate infusion of 0.35 microgram/min/kg at 0.036 ml/min. Treatment A consisted of a 90-min equilibration period and first hour (Phase I) of study in which animals were maintained under euvolemic conditions. During the subsequent 3 hr of Treatment A (Phase II), animals were maintained under hydropenic conditions. These experiments were then repeated 1 week later (Treatment B) with the temporal aspects of hydration reversed (Phase III, hydropenia; Phase IV, euvolemia). Serial plasma and urine samples were assayed for bumetanide by high-performance liquid chromatography (HPLC) and for sodium by flame photometry. The bumetanide excretion rate was not significantly different during the 4 hr of Treatment A, although minor differences were observed between Phase III and Phase IV of Treatment B. The sodium excretion rate showed significant differences between euvolemic and hydropenic conditions of both treatments. A two- to threefold difference in the sodium excretion rate persisted even when slight differences (less than 20%) in bumetanide excretion rates were taken into account. These results demonstrate that an acute tolerance does develop to constant-rate infusions of bumetanide when inadequate fluid and electrolyte replacement occurs and that this tolerance can be reversed by rehydration.