A number of organic acid compounds such as loop diuretics have been shown to adversely effect cochlear function in patients as well as in experimental animal models. Unfortunately, the molecular basis for these ototoxic effects has not yet been elucidated. Recent experimental findings have suggested that certain organic acid compounds can reduce the cochlear effects of furosemide. The proposed research will examine the interaction of organic acid transport inhibitors with two ototoxic loop diuretics: ethacrynic acid and furosemide. The studies will investigate whether such interactions result in a reduced cochlear effect of these ototoxic loop diuretics. The specific electrophysiologic experiments will look at changes in endocochlear potential, eighth nerve action potential, and the measurement of potassium and chloride concentration in endolymph using ion sensitive microelectrodes. Correlation of these findings with the ultrastructure of the stria vascularis will be made. The blood levels of loop diuretics will be measured in controls and experimental animals to determine whether they are altered by drugs which reduce the cochlear effects. In addition, the diuretic response in control and experimental animals will be evaluated to determine whether drugs which alter the cochlear effects also change the diuretic response to loop diuretics. The findings that specific inhibition of undesirable ototoxic effects of loop diuretics without changing the pharmacokinetics or desired pharmacodynamic effect will strongly suggest the presence of a carrier for organic acids in the cochlear, analogous to that seen in other tissues. Furthermore, such findings would have extremely provocative therapeutic implications. The possibility of manipulation of ototoxic effects of loop diuretics without altering the necessary response of removing excess fluid from the patient would be of major clinical importance.
