The effects of inhibition of the strial Na+-K+-activated ATPase by perilymphatic ouabain in the guinea pig.

The endolymphatic effects of perilymphatic ouabain (2 X 10(-3) M) were followed in 3 guinea pigs using ion-sensitive micro-electrodes, enabling a Na+-related permeability increase to be identified. Investigation of the strial ultrastructural changes in 11 more animals revealed early swelling of the marginal cells, while the intermediate and basal cells became shrunken with characteristically dark-staining cytoplasm. The subsequent cellular alterations were complex. The findings suggest that a major function of the Na+-K+-activated ATPase is preservation of the normal intracellular environment, inhibition resulting in widespread indirect effects. General measures of strial function, consequently, do not document just ATPase inhibition.

The time course of the strial changes produced by intravenous furosemide.

The ultrastructural abnormalities produced in the stria vascularis by intravenous furosemide (80 mg/kg) were investigated in 14 guinea pigs. The changes consisted of marginal cell swelling, shrinkage of the intermediate cells and enlargement of the intercellular spaces, as described in other intoxications. The cytological derangements (including characteristic dilatation of the Golgi membranes) differed in detail from those arising after a comparable dose of ethacrynic acid. The morphological alterations were already present at 2 min, were maximal at 10 min, recovered only slowly at first and had not disappeared entirely at 180 min. For comparison, the fall in the endocochlear potential had a latent period of 20 s and was greatest at 2.3 min; its recovery was rapid initially but also incomplete at 180 min. Thus, no gross discrepancy in the time courses occurred, even if the correlation was imperfect. That reported previously must be due, therefore, to the much longer delays found following intraperitoneal administration.

The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system. I. Functional aspects.

The endolymphatic changes produced by an intravenous injection of 60 mg kg-1 ethacrynic acid were followed for up to 120 min using conventional and ion-sensitive (Na+, K+ and pH) microelectrodes in the rat. They were found to be caused by three distinct effects upon the endolymph system. Initially, the drug completely inhibited the strial potential-producing and cation-transporting processes. Recovery began quickly and was rapid at first. Then its rate declined considerably, probably due to diminution in strial energy production of delayed onset and prolonged duration. Coincident with these actions upon active transport, there was a decrease in the overall cation permeability of the endolymph system. This followed a different time course and affected K+ much more than Na+. The findings also provided further information about the mechanisms responsible for the normal endolymphatic composition. Qualitatively similar results were obtained in a subsidiary study on guinea pigs.

The nature of the ototoxic actions of ethacrynic acid upon the mammalian endolymph system. II. Structural-functional correlates in the stria vascularis.

The relationship of the ultrastructural changes in the stria vascularis to the functional alterations in the endolymph system was investigated in 23 rats at various times up to 120 min after a single intravenous injection of ethacrynic acid (60 mg kg-1). The overall effect upon the marginal cells, revealed by the development and regression of marked cytoplasmic swelling, was reasonably well correlated with the derangements produced in the strial ion-transporting mechanisms. The pathophysiological relationships of the action upon the intermediate cells was less exact and no unequivocal structural correlates were found for the diminution in membrane permeability and the probable late decrease in energy production. The size of the interstitial spaces was determined mainly by the variations in volume of the marginal and intermediate cells.

The nature of the negative endocochlear potentials produced by anoxia and ethacrynic acid in the rat and guinea-pig.

1. The alterations in the Na+ and K+ concentrations of the cochlear endolymph and in the endocochlear potential were followed simultaneously by means of ion-sensitive and conventional micro-electrodes during simple anoxia, during anoxia after i.v. ethacrynic acid and after i.v. ethacrynic acid alone. The endolymphatic pH changes were measured separately and the effect of perilymphatic ethacrynic acid upon the endocochlear potential was investigated. 2. The over-all Na+:K+ permeability ratio for the endolymph system was determined in individual animals for the first time using an indirect method. The normal mean values of 0.27 (rat) and 0.38 (guinea-pig) were increased after ethacrynic acid. Permeability changes occurred during anoxia but were delayed in onset. 3. The negative endocochlear potentials in each situation behaved quantitatively like modified K+ diffusion potentials largely dependent upon the K+ and Na+ gradients between endolymph and perilymph.

A study of the electrochemistry and osmotic relationships of the cochlear fluids in the neonatal rat at the time of the development of the endocochlear potential.

1. Changes in the endocochlear potential between the 8th and 18th days after birth were investigated in the rat. Initially the potential was low but its magnitude increased rapidly between the 11th and 16th day. During the 13th and 14th days the rate of increase was approximately 1 mV/hr.2. The rapid potential increase arose virtually simultaneously in all three turns of the cochlea.3. Histological examination revealed the cochlea, including the hair cells of Corti's organ and the stria vascularis, to be fully mature before the period of rapid change in the endocochlear potential, apart from the cells of Claudius, whose final development coincided with the latter part of this phase.4. The endolymphatic sodium concentration (average 1.0 m-equiv/l.) had attained the very low adult level in the earliest period studied. The potassium and chloride concentrations were slightly below the normal adult levels, the result of some degree of general hypo-osmolality present at this time.5. The endolymphatic ionic concentrations remained unchanged during the phase of rapid increase in the endocochlear potential.6. The findings thus indicate that the distinctive endolymphatic ionic composition and the endocochlear potential arise largely independently and in succession during cochlear maturation.7. No differences in osmotic pressure were demonstrated between endolymph, perilymph and serum. The problems concerning the homoeostasis of the inner ear fluids do not consequently seem to be complicated by unusual hydrodynamic aspects.8. Alterations in body fluid osmolality, produced by intraperitoneal injection of water or hypertonic glycerol, were accompanied by simultaneous changes in the osmotic pressures of the inner ear fluids. Some portion of the membranes bounding the endolymphatic space is therefore considered to be freely permeable to water.9. The investigations provide no further information about the nature of the endocochlear potential, although an increase in the electrical resistance of the cochlear duct membranes is thought responsible for its appearance. The time relationships of this period support the concept that the potential is an essential feature of the mechano-electric transduction process.