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Electrophysiology of the cochlea.

With careful techniques it is possible to demonstrate three electric potential regions of the inner ear: an intracellular negative potential, a high positive potential in the endolymph that appears bounded at the scala media side of the tectorial membrane rather than at the reticular lamina, and the extracellular spaces, which contain a fluid at near zero potential. The tectorial membrane is also found to be at zero potential. Further research may yet uncover more details of the resting potential distribution as we become expert at placing microelectrodes and learn better ways of correlating potential with position. Surely the study of these resting potentials would contribute to our understanding of the mechanisms of fluctuant hearing loss because these first order potentials are intimately related to the state of health of the inner ear.

Action Potentials↗

Morphology of the endolymphatic duct and sac in the Mongolian gerbil.

A light microscopical study of the endolymphatic duct and sac of the Mongolian gerbil is presented. This animal model was studied because of its tendency to develop a condition of body fluid imbalance which may represent a hazard to the inner ear fluid environment. Particular stress is laid on the combination of the lack of an extraosseous endolymphatic sac and the presence of elastic tissue in the subepithelial space of the sac. These findings highlight the role of this structure for the regulation of the pressure within the inner ear. Lastly, a secretory process is proposed by which a homogeneous precipitate produced in the lumen of the sac can regulate volume and pressure changes.

Animals↗

Structure and innervation of the cochlea.

The role of the cochlea is to transduce complex sound waves into electrical neural activity in the auditory nerve. Hair cells of the organ of Corti are the sensory cells of hearing. The inner hair cells perform the transduction and initiate the depolarization of the spiral ganglion neurons. The outer hair cells are accessory sensory cells that enhance the sensitivity and selectivity of the cochlea. Neural feedback loops that bring efferent signals to the outer hair cells assist in sharpening and amplifying the signals. The stria vascularis generates the endocochlear potential and maintains the ionic composition of the endolymph, the fluid in which the apical surface of the hair cells is bathed. The mechanical characteristics of the basilar membrane and its related structures further enhance the frequency selectivity of the auditory transduction mechanism. The tectorial membrane is an extracellular matrix, which provides mass loading on top of the organ of Corti, facilitating deflection of the stereocilia. This review deals with the structure of the normal mature mammalian cochlea and includes recent data on the molecular organization of the main cell types within the cochlea.

Animals↗

Method for computing motion in a two-dimensional cochlear model.

We describe an effective technique for computing the steady-state motion in a two-dimensional cochlear model. With the cochlear fluid assumed incompressible and inviscid, the problem reduces to solving Laplace's equation for a region with a yielding boundary (corresponding to the basilar membrane). From an integral equation representation of this solution, a pair of second-order differential equations is derived. The solution of these differential equations gives the velocity of the basilar membrane and hence other related quantities, e.g., displacement, pressure, driving-point impedance at the stapes. Higher-order approximations, as well as extensions to nonlinear membranes are discussed.

Acoustic Stimulation↗

The low-frequency response of inner hair cells in the guinea pig cochlea: implications for fluid coupling and resonance of the stereocilia.

AC receptor potentials within the inner hair cells of the basal turn of the guinea pig cochlea have been recorded for stimuli in the frequency range 20 Hz to 3200 Hz. Comparison of these potentials with potentials recorded in scala media suggests that the stereocilia of many inner hair cells are stimulated by the transverse velocity of the cochlear partition for very low frequency, but above a transition frequency in the range 400 Hz to 1000 Hz they become entrained with partition displacement. It is suggested that such a transition is probably a simple consequence of the fluid coupling that drives these cells, and that mechanical resonance of the free-standing stereocilia of the inner hair cells does not occur in the basal turn of the guinea pig. These results do not, however, preclude the possibility of mechanical resonance involving the stereocilia of the outer hair cells. The results also indicate that the bodies of these cells low-pass filter the intracellular receptor potential, with a cutoff frequency of approximately 1000 Hz.

Acoustic Stimulation↗

Correlation of amikacin concentrations in perilymph and plasma of continuously infused guinea pigs.

A commercially available radioimmunoassay kit was modified to enable us to measure, in triplicate, the amikacin concentration in 1 microliter of perilymph fluid. Amikacin levels in plasma and perilymph were measured in guinea pigs after continuous intravenous infusion at four different dosing rates. After a 4-h infusion, a good linear correlation was found between the amikacin concentration in plasma and the dosing rate. Likewise, a significant linear relationship was found between concentrations of amikacin in perilymph and plasma (y = 0.21x + 2.56; r = 0.67; n = 45) after 6 h of infusion. These results suggest nonsaturation kinetics at the concentrations used.

Amikacin↗

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.

Animals↗

Pharmacokinetics of aminoglycoside antibiotics in blood, inner-ear fluids and tissues and their relationship to ototoxicity.

This review critically evaluates the literature on aminoglycoside pharmacokinetics in order to answer the question how fluid and tissue levels of the drugs relate to the development of ototoxic and nephrotoxic side effects. We will summarize the evidence that: (1) aminoglycosides do not accumulate in inner-ear fluids; (2) aminoglycoside levels in fluids do not correlate with the ototoxic potential of a drug, and (3) selective toxicity cannot be explained by selective tissue penetration of the drugs. We suggest that studies of drug disposition at the cellular level after chronic aminoglycoside treatment be conducted to establish whether a cell-specific uptake contributes to the selective toxicity of the aminoglycoside antibiotics. A sequence of biochemical events that may lead to the development of toxicity at the molecular level is briefly described.

Aminoglycosides↗

Ethacrynic acid facilitates gentamicin entry into endolymph of the rat.

Influence of ethacrynic acid (EA) upon gentamicin kinetics in perilymph and endolymph was studied in rats that were given a constant-infusion of gentamicin (150 micrograms/min) and EA (140 micrograms/min). Inner ear fluids and plasma were sampled up to 5 h. The purity of the endolymph was ensured by measurement of sodium and potassium concentrations. Gentamicin assay was done with a modified radioimmunoassay. Results show that EA facilitates the entry of gentamicin into endolymph, while it does not affect the kinetics of the drug in perilymph. Although the mechanism of this facilitation remains unclear, this result may account for the ototoxic potentiation reported between EA and aminoglycoside antibiotics.

Animals↗

[Effects of mannitol on the fluids of the internal ear. Use in the treatment of deafness].

The action of mannitol upon the inner ear fluids was studied experimentally by means of kinetics of mannitol entry into cochlear perilymph and endolymph in rats. A daily two hours infusion of 10% mannitol induces an osmotic water flow from cochlear fluids toward plasma. Following this therapeutic protocol, progressive, non-tumoral sensorineural hearing loss is enhanced in 32% of the cases. The rate of hearing improvement is larger than 50% in case of Ménière's disease. For sudden hearing loss, 75% of the cases are improved by mannitol, and 92% of the cases when the delay between the hearing loss onset and the mannitol therapy is less than two weeks. Sudden hearing loss should be considered as a sensory emergency.

Adult↗

Antigenicity and protein content of perilymph in acoustic neuroma patients.

11 acoustic neuroma patients, exhibiting cell-mediated immunity in vitro against acoustic neuroma extract, were tested for cell-mediated immunity in vitro against perilymph samples from other acoustic neuroma patients. 14 of 21 perilymph samples were antigenic. None of three healthy persons reacted against antigenic perilymph samples. The perilymph antigenicity was reproducible and negatively correlated to the perilymph sample volume. Differences in sample volume could not be ascribed to admixture of endolymph, cerebrospinal fluid, plasma or blood. The perilymph protein concentration varied from 31 to 54 g/l. Gel electrophoresis of perilymph proteins revealed less staining in the alpha-region compared to plasma proteins and a distinct band in the pre-gamma region absent in plasma. Tau-transferrin was not detected in any of 13 samples. The findings support that the cell-mediated immune response against acoustic neuroma extract may be mediated through release of antigen(s) to the perilymph.

Adolescent↗

X-ray microanalysis of inner ear fluids in the embryonic and newborn guinea pig.

In energy-dispersive histograms, changes in the relative peak intensities were followed, especially C1 and K, which indicate the maturation of endolymph. The maturation of endolymph in the guinea pig occurs prior to birth. In X-ray histograms, distinct peaks for C1 and K, but also for Na, were observed approximately 20 days before (DBB). The lesser relative peak intensities for C1 and K as compared with mature endolymph indicate an immature endolymph composition at this stage of development. The relative peak intensities of C1 and K increased at approximately the 10-DBB stage and showed similar values as at birth.

Animals↗

Intracellular and extracellular ion content of the endolymphatic sac.

The Cl- activity in the endolymph of the endolymphatic sac and in the cochlear duct was measured with Cl- sensitive double-barreled microelectrodes. The Cl- activity in the endolymphatic sac fluid was lower than in the cochlear duct. A small, positive, DC potential was recorded in the endolymphatic sac. During anoxia, the DC potential decreased while the Cl- activity in the endolymphatic sac increased. The K/Na ratio in the epithelial cells and subepithelial tissue of endolymphatic sac was measured using the LAMMA technique. The K/Na ratio in the epithelial cells decreased after ethacrynic acid injection (60 mg/kg i.v.). These findings suggest that chloride in the endolymphatic sac is actively transported inward and outward.

Animals↗

The importance of potassium in the function of frog semicircular canals.

The slow potentials and afferent discharge of impulses in frog semicircular canals have been studied at different endolymphatic and perilymphatic K+ concentrations. Results indicate that the presence of K ions in the bathing fluids is essential for maintaining the receptor function in crista ampullaris, although very low concentrations of this ion in the perilymph are sufficient to preserve the receptor responsiveness to mechanical stimuli. The hypothesis is put forward that K+ may be pumped from the exterior of the canal towards the intracupular structures, where it accumulates. A K-rich endolymphatic environment does, however, appear to be necessary to ensure the resting activity of ampullar receptors and their ability to be "disfacilitated" during inhibitory cupula deflections.

Action Potentials↗

Effects of intravenous glycerol injection on inner ear fluid electrolytes.

Under sodium pentrobarbital anesthesia (20-30 mg/kg, i.p.), normal guinea pigs received an intravenous injection of glycerol (1.0 ml/kg). Serum, cerebrospinal fluids (CSF) and inner ear fluids were collected from the scala tympani perilymph, scala vestibuli perilymph and the scala media endolymph. The sodium and potassium concentrations were assessed using microflame photometry. Increases in sodium concentration were found in the CSF and the scala tympani perilymph; no significant changes were observed in the serum, scala vestibuli perilymph or the scala media endolymph. These sodium increases were considered to be a result of the dehydration process caused by the osmotic agent glycerol. Increases in potassium concentration were found only in the scala vestibuli perilymph.

Animals↗

Biochemical aspects of inner ear fluids and possible implications for pharmacological treatment.

Inner ear fluids are in dynamic equilibrium with surrounding fluids, namely blood and cerebrospinal fluid. It is known that substances injected into the blood stream or cerebrospinal fluid are transported into the inner ear fluids. The rate of transport from blood into perilymph is inversely related to the molecular weight or molecular size. There appears to exist a blood-labyrinth barrier. In general, the morphology of capillaries in the spiral ligament and stria vascularis is similar to that of brain capillaries which contribute to formation of the blood-brain barrier. Information on the volume of the inner ear fluids is necessary for estimating the toxicity of the drugs as well as the effective concentration of systemically injected substances. Recently, alteration of the levels of arachidonic acid metabolites, especially the prostaglandins, in perilymph under experimental conditions has been reported. The responses of prostaglandin levels in perilymph to these experimental conditions (aspirin injection, antidiuretic hormone or epinephrine infusion) suggest that prostaglandins may play an important role under physiological conditions. Possible mechanisms of auditory dysfunction due to abnormal prostaglandin metabolism in the auditory system are discussed.

6-Ketoprostaglandin F1 alpha↗

The cochlear amplifier as a standing wave: "squirting" waves between rows of outer hair cells?

This paper draws attention to symmetric Lloyd-Redwood (SLR) waves-known in ultrasonics as "squirting" waves-and points out that their distinctive properties make them well-suited for carrying positive feedback between rows of outer hair cells. This could result in standing-wave resonance-in essence a narrow-band cochlear amplifier. Based on known physical properties of the cochlea, such an amplifier can be readily tuned to match the full 10-octave range of human hearing. SLR waves propagate in a thin liquid layer enclosed between two thin compliant plates or a single such plate and a rigid wall, conditions found in the subtectorial space of the cochlea, and rely on the mass of the inter-plate fluid interacting with the stiffness of the plates to provide low phase velocity and high dispersion. The first property means SLR wavelengths can be as short as the distance between rows of outer hair cells, allowing standing wave formation; the second permits wide-range tuning using only an order-of-magnitude variation in cochlear physical properties, most importantly the inter-row spacing. Viscous drag at the two surfaces potentially limits SLR wave propagation at low frequencies, but this can perhaps be overcome by invoking hydrophobic effects.

Basilar Membrane↗

K, Cl, and H2O entry in endolymph, perilymph, and cerebrospinal fluid of the rat.

The kinetics of radioactive potassium, chloride, and water entry into endolymph, perilymph, and cerebrospinal fluid were studied after intravenous administration of tracers in anesthetized and nephrectomized rats. Samples of cochlear endolymph, perilymph of scala vestibuli, perilymph of scala tympani, and cisternal cerebrospinal fluid were obtained. The data showed: 1) a rapid turnover of water in endolymph, perilymph, and cerebrospinal fluid, since 3H2O equilibrated with plasma in a few minutes; 2) a slow entry of 42K and 36Cl in perilymph, since 36Cl equilibrated with plasma after 2 h and 42K did not at 6 h; 3) an extremely slow entry of 42K and 36Cl in endolymph, since no equilibrium with plasma was obtained within the 5 h of the experiments. The comparison of the compartmental analysis of our data with the results of other studies using perilymphatic perfusion of tracers indicated that perilymph rather than plasma may be considered as the precursor of endolymph.

Animals↗