Dose-response relationships for furosemide ototoxicity in rat

Furosemide is an ototoxic loop diuretic which is highly bound to serum albumin. Previous studies have shown that rats deficient in albumin are more susceptible to furosemide ototoxicity than are rats with normal serum albumin concentrations. The present study was designed to compare the dose-response relationships for furosemide ototoxicity in rats with normal serum albumin concentration to rats without albumin in their serum. Young adult rats 50-80 days of age from each group were anesthetized with Rompun, and the endocochlear potential (EP) and compound action potential (CAP) thresholds were measured before and after furosemide injection. Afer a stable EP and CAP threshold were measured, each animal was injected with a single dose of furosemide through a cannula in the jugular vein. Rats with normal serum albumin had very little change in the EP or CAP threshold until the dose of furosemide was 40 mg/kg or greater. The dose-response curves for EP reduction and CAP threshold elevation then rose steeply to reach a maximum at 50 mg/kg. Albumin-deficient rats were much more sensitive to the effects of furosemide. The dose-response curves for both EP and CAP were shifted to the left. The doses resulting in half-maximal effects in the albumin-deficient rats were about half that found in the normal rats. These findings support the hypothesis that the access of furosemide to its site of ototoxic action in the cochlea depends on the quantity of unbound furosemide in the serum.