Effect of Ethacrynic Acid, Furosemide, and Ouabain Upon the Endolymphatic Potential and Upon High Energy Phosphates of the Stria Vascularis

Abstract

The loop diuretics ethacrynic acid (EA) and furosemide (FU) were applied systemically to guinea pigs at dosages from 10–100 mg/kg. At high dosages the endolymphatic potential (EP) invariably turned negative. When the EP had reached maximum negative values due to EA, the ATP levels of the stria vascularis were moderately reduced, but P‐creatine levels were normal. In the case of FU both high energy phosphates remained at normal levels. When EA and FU intoxicated ears were subjected to ischemia, the rate of decline of ATP and P‐creatine was markedly less than the ischemic decline in nonintoxicated ears. These results suggest a strong interference with energy utilization, and in the case of EA a moderate impairment of energy generation. In severe intoxication by perilymphatically applied ouabain (10−3 M) strial ATP remained normal but P‐creatine was significantly increased. The reduction of the ischemic decline rate in ouabain intoxicated ears was even more marked than in the case of EA or FU, indicating a very strong interference with energy utilization, presumably due to complete inhibition of Na+K+‐ATPase. The I50 of the endolymphatic potential with regard to perilymphatically applied EA and FU was found to be 10−5 M and 2 x 10−4 M respectively. By K contrast, strial Na+K+‐ATPase was 50% inhibited with 5 x 10−3 M EA and not inhibited at all by FU. It is therefore unlikely that the effect of loop diuretics upon the endolymphatic potential is due to interference with strial Na+K+‐ATPase.

Distribution of the Na,K-ATPase α Subunit in the Rat Spiral Ganglion and Organ of Corti

“…Perilymphatic perfusion of ouabain, an inhibitor of the NKAα, causes a rapid reduction of the endocochlear potential (Konishi and Mendelsohn 1970;Kuijpers and Bonting 1970;Kusakari et al 1978), and researchers have identified NKAα1 in the strial marginal cells and NKAα2 in the lateral wall fibrocytes (McGuirt and Schulte 1994;Schulte and Steel 1994; reviewed in Wangemann 2006). The contribution of the NKAα1 and NKAα2 in maintaining the endocochlear potential is supported by the characterization of mice carrying deletions of these subunits.…”

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

“…The processes of HC death, survival, and repair/regeneration can also be further examined and manipulated in genetically modified animals with the goal of improving our understanding of the underlying molecular mechanisms. (Brown and McElwee 1972;Kusakari et al 1978a;Wangemann 1995). Furosemide, and other loop diuretics such as bumetanide, causes an acute enlargement of the intrastrial space (Santi and Duvall 1979;Pike and Bosher 1980;Santi and Lakhani 1983) in association with a decline in the positive endocochlear potential (EP; Kusakari et al 1978a, b).…”

Mice Lacking the Basolateral Na-K-2Cl Cotransporter Have Impaired Epithelial Chloride Secretion and Are Profoundly Deaf

“…In the inner ear, NKCC1 is expressed at high levels on the basolateral membrane of marginal cells of the stria vascularis (15,16). K ϩ secretion by marginal cells is responsible for the high concentrations of K ϩ in the endolymph and for the endocochlear potential, which is eliminated by perilymphatic or systemic application of bumetanide or furosemide (17)(18)(19). These observations and the ototoxicity of loop diuretics (20) suggest that NKCC1 contributes to the high rates of K ϩ uptake needed to maintain K ϩ currents across the apical membrane of the marginal cell and that NKCC1 plays a critical role in hearing.…”