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Ototoxicity resulting from combined administration of cisplatin and gentamicin.

The hypothesis that cisplatin can augment the ototoxicity of gentamicin was tested. Seven groups of 11 guinea pigs each were given a single dose of cisplatin either alone or 14 days before, at the beginning, midway through, or at the end of a course of gentamicin administered daily for 14 days. Blood and perilymph gentamicin and cisplatin concentrations were determined in three of the animals from each group. Auditory damage was determined in the remaining 8 animals electrophysiologically by measuring the compound action potential and alternating-current cochlear potential. Hair cell damage was determined using the surface preparation technique. An augmented ototoxic effect occurred when the cisplatin was given early in the 14-day course of gentamicin and did not occur when it was given at the end of treatment.

Acoustic Stimulation↗

The relation between the endocochlear potential and spontaneous activity in auditory nerve fibres of the cat.

The relation between the endocochlear potential and spontaneous discharge rate in auditory nerve fibres was determined following intravenous injections of furosemide in anaesthetized cats. Following furosemide administration, both the endocochlear potential and the spontaneous discharge rates of auditory nerve fibres decreased synchronously. The logarithm of the spontaneous discharge rate was proportional to the endocochlear potential. The slope of the logarithmic relation increased as a function of the characteristic frequency of the fibre. The slope of the logarithmic relation is steeper for fibres with 'medium' spontaneous discharge rates (0.5-12 spikes/s) than for fibres with 'high' spontaneous discharge rates (greater than 18 spikes/s). Among high spontaneous rate fibres, the slope does not appear to vary systematically with the spontaneous rate of the fibre. The decrease in spontaneous discharge rate in auditory nerve fibres is interpreted as follows: (1) the injection of furosemide causes a decrease in the endocochlear potential, (2) a decrease in the endocochlear potential produces a linearly related hyperpolarization of the membrane potential of the hair cell by altering the standing current which flows through the transducer membrane, and (3) the logarithm of the rate of release of transmitter quanta decreases with the hyperpolarization of the membrane potential of the hair cell, which decreases the rate of occurrence of action potentials at the hair cell afferent junction.

Action Potentials↗

Dynamics of the flow of perilymph in the cochlea of the guinea pig.

The dynamics of perilymph flow in the cochlea was studied in guinea pigs. After placement of sodium chloride crystals on the round window membrane, the potassium ion concentration in the scala vestibuli in the basal turn does not change. The potassium ion concentrations in the scala tympani in the basal turn increases rapidly, while the potassium ion concentration in the scala tympani in the third turn increases slowly and to a lesser extent. The cochlear microphonic potential decreases in the basal turn and to a lesser extent in the third turn. After placement of sodium chloride on the fenestra in the scala tympani of the third turn, the chochlear microphonic potential in the basal turn does not change. These data lend support to the theory of longitudinal flow of perilymph in the scala tympani.

Animals↗

Comparative ototoxicities of gentamicin and netilmicin in three model systems.

The ototoxic potentials of netilmicin and gentamicin were compared in three models: the standard in-vivo animal model (guinea pig), organ culture of the embryonic inner ear (mouse), and perilymphatic perfusions (guinea pig). Toxicity was assessed by light and electron microscopy of hair cells or by measurement of cochlear microphonic potentials. In vivo, netilmicin did not have any significant morphologic effect on hair cells under conditions (dose X duration) where gentamicin caused excessive hair cell loss. In organ culture, concentrations of netilmicin had to be at least tenfold higher than those of gentamicin in order to produce comparable damage. In direct applications of the drugs to the cochlea by perilymphatic perfusion, similar effects on cochlear microphonics were seen when netilmicin concentrations were more than threefold higher than those of gentamicin. It is suggested that netilmicin ototoxicity observed in vivo is low because of lesser penetration into the inner ear and lower intrinsic toxicity.

Animals↗

Determination of auditory thresholds in the brushtail possum (Trichosurus vulpecula).

The auditory abilities of the brushtail possum (Trichosurus vulpecula) have been measured by cochlear potential readings, but no behavioural determinations of their auditory abilities have been published. Six experimentally naive possums were trained to perform a two-response conditional discrimination between the presence and absence of an 880-Hz tone (at 80 dB). All six possums readily learned this task. The behavioural threshold for this tone was determined using a modified tracking procedure and found to be similar to that reported using cochlear microphonic potentials. One concern with the current method was the communal nature of the experimental environment so a further threshold determination in a sound-attenuating chamber was conducted. No substantial difference was noted between the results obtained in the two threshold determinations. The success of the current method means that a full, behavioural audiogram for the brushtail possum, which would complement the existing cochlear potential data, is now possible.

Animals↗

Modifications of cochlear microphonic frequency responses following transient changes of hydrostatic pressure in the perilymph.

Cochlear microphonic potential was recorded with differential electrodes implanted in the various turns of the guinea-pig cochlea. Isointensity frequency responses were plotted in normal conditions and after excessive displacements of the cochlear partition. These displacements were provoked by changes of hydrostatic pressure in the perilymph of scala tympani or scala vestibuli. Typical modifications of the frequency response were observed. The most noticeable was a division in two parts of the response zone which suggested the existence of two resonance peaks. Scanning electron microscopy revealed that changes of hydrostatic pressure provoked alterations of the stereocilia in the outer rows of external hair cells, probably in relation with a decoupling of the tectorial membrane from the organ of Corti. These results are discussed in terms of possible alterations of cochlear micromechanics.

Animals↗

Are aminosugars ototoxic?

The ototoxicity of the kanamycin fragment 3-amino-3- deoxy-D-glucose (3-aminoglucose, kanosamine), was investigated by perilymphatic perfusion in the guinea pig. Concentrations of 10 or 28 mM of this compound had no effect on cochlear microphonic potentials (CM), contrasting with previous observations (Owada 1962). Kanamycin at 1 mM decreased CM significantly under otherwise identical conditions. The action of kanamycin was at least partially reversible.

Animals↗

Cochlear dysfunction in the jerker mouse.

Surface preparations show that the jerker (je/je) mutant mouse has a normal total number of cochlear hair cells when young but that these progressively degenerate with increasing age. However, no gross 8th nerve action potentials or cochlear microphonics could be detected at the round window in 12-20-day-old mutants, although many hair cells still appear to be intact at these ages. Light microscopy of surface preparations is apparently a poor indicator of the functional state of hair cells, at least in genetically determined inner ear defects. The endocochlear potential (EP) was significantly higher in the mutants than in controls during the maturation of the cochlea. During anoxia induced in adults, EP fell to a significantly less negative value in mutants than in control mice. This abnormality in the anoxia potential probably reflects an organ of Corti abnormality.

Age Factors↗

Effects of putative transmitters on afferent cochlear transmission.

Putative transmitters and related substances were perfused through the guinea pig scala tympani while monitoring the compound action potential of the cochlear nerve (AP) and the cochlear microphonic potential. Various substances were then ranked according to their ability to reduce the AP. The more active compounds ranked: methysergide (1 mM) greater than ATP (10 mM) = tyramine (10 mM) greater than salicylate (10 mM) greater than bicuculline (10 mM) greater than asparate (10 mM) greater than glutamate (10 mM) greater than citrate (10 mM) greater than dextrose (100 mM) greater than glycine (100 mM) greater than GABA (100 mM) greater than prostaglandin E2 (1 mM) greater than serotonin (10 mM). The activity of substances at 100 mM indicates a physical, osmotic change in the cochlear structure. Activity at 10 mM and 1 mM indicated afferent transmitter-like activity for the putative transmitters and interference with the endogenous transmitter for related substances. It is concluded that several substances can be eliminated as afferent transmitter candidates, while others warrant further examination.

Action Potentials↗

Gentamicin ototoxicity dissociated from glucose uptake and utilization.

The hypothesis was tested that gentamicin causes loss of cochlear microphonic potentials by interfering with glucose transport or metabolism in cochlear structures. Gentamicin (3 or 10 mM), applied by perilymphatic perfusion in the guinea pig, reduced cochlear microphonics in a dose-dependent manner. The presence of 5 mM glucose lowered the initial rate but not the final (60 min) loss of cochlear microphonics. Glucosamine (2-deoxy-2-aminoglucose), a reported inhibitor of glucose transport, had no effect at concentrations as high as 20 mM. Glucose utilization was measured by introducing radiolabeled deoxyglucose into the perfusate and determining its uptake into inner ear tissues. Concentrations of deoxyglucose-6-phosphate in organ of Corti and in stria vascularis increased linearly with time and remained unaffected by the presence of 3 mM gentamicin. Ten mM gentamicin reduced deoxyglucose uptake by 30% in the lateral wall tissues but not in the organ of Corti preparation. The lack of correlation between loss of microphonics and glucose utilization does not support interference with glucose metabolism as a primary mechanism of aminoglycoside ototoxicity.

Animals↗

Hearing loss and visco-elasticity of middle ear fluid.

It has been suggested that the physical properties of middle ear effusion--its viscosity and elasticity--affect the degree of conductive impairment. Exogenous mucus having substantial visco-elasticity was instilled in the bullae of guinea pigs, and the resulting hearing loss was determined by measurements of the cochlear microphonic potential. In this preparation the hearing loss induced by mucus did not differ significantly from that found when the bulla was filled with saline. We find no evidence of a relationship between visco-elasticity of middle ear fluid and amount of conductive impairment.

Animals↗

The development of a single frequency place in the mammalian cochlea: the cochlear resonance in the mustached bat Pteronotus parnellii.

Cochlear microphonic potentials (CMs) were recorded from the sharply tuned, strongly resonant auditory foveae of 1- to 5-week-old mustached bats that were anesthetized with Rompun and Ketavet. The fovea processes Doppler-shifted echo responses of the constant-frequency component of echolocation calls. During development, the frequency and tuning sharpness of the cochlear resonance increases, and CM ringing persists for longer after the tone. CM is relatively insensitive at tone onset and grows linearly with increased stimulus level. During the tone, the CM is more sensitive and grows compressively with increased stimulus level and phase leads onset CM by 90 degrees for frequencies below the resonance. CM during the ringing is also sensitive and compressive and phase leads onset CM by 180 degrees below the resonance and lags it by 180 degrees above the resonance. Throughout postnatal development, CMs measured during the tone and in the ringing increase both in sensitivity and compression. The cochlear resonance appears to be attributable to interaction between two oscillators. The more broadly tuned oscillator dominates the onset response, and the narrowly tuned oscillator dominates the ringing. Early in development, mechanical coupling between the oscillators results in a relatively broadly tuned system with several frequency modes in the CM at tone onset and in the CM ringing. Beating occurs between the resonance and the stimulus response during the tone and between two components of the narrowly tuned oscillator at tone offset. At maturity, the CM has three modes for frequencies within 10 kHz of the resonance at tone onset and a single, sharply tuned mode in the ringing.

Acoustic Stimulation↗

[Value of the study of cochlear microphonic recordings in deep and severe deafness].

A study was conducted to assess the contribution of cochlear microphonic potential recordings during electrophysiologic audiometry examinations. Amplitude of microphonic recordings were correlated with the degree of deafness, its etiology, and the prosthetic prognosis in 38 electrocochleographic examinations. Preliminary results are analyzed.

Cochlear Microphonic Potentials↗

Cochlear microphonic responses of the peripheral auditory system to frequency-varying signals.

Cochlear partition displacement responses to rising and falling frequency sweeps were inferred from cochlear microphonic potentials recorded from three basal turn locations in the guinea pig cochlea. Relative phase measures of microphonic potentials recorded from the three locations suggested that displacements of the partition toward either scala vestibuli or scala tympani occurred closely together in time for rising sweeps and were dispersed in time for falling sweeps. These differences in peripheral response patterns to sweeps may explain, in part, asymmetric neural discharges elicited from higher neural centers.

Animals↗

Components of cochlear electric responses in the alligator lizard.

Electric responses to clicks and tones were recorded at the round windows of anesthetized alligator lizards before and after tetrodotoxin (TTX) was added to scala tympani. By combining click responses obtained in the presence and absence of TTX and at high and low click repetition rates, we trisected click responses into three components: (1) a rate-insensitive, TTX-insensitive component (that we identify as the cochlear microphonic potential or CM); (2) a rate-sensitive, TTX-sensitive component (that we identify as the neural component); (3) a rate-sensitive, TTX-resistant component (which has not been identified previously and which we call component X). Component X is generated in the inner ear and has a latency between that of the CM and the neural component. Several possible origins for component X are discussed of which the most likely is that component X represents the compound post-synaptic potential of the nerve terminals. Measurements of responses to tones in the presence and absence of TTX demonstrate that the contribution of the neural component to the response is appreciable below 1.5 kHz and negligible above this frequency.

Animals↗

Comparative ototoxic effects of RU 25434, amikacin and neomycin in guinea-pigs.

The ototoxic effects of RU 25434, a new semi-synthetic aminoglycoside antibiotic, were compared to those of amikacin and neomycin. Experiments were performed in adult and new-born guinea-pigs, ototoxicity being assessed by Preyer's reflex response and the measurement of the cochlear microphonic potentials at the end of treatment. The well known ototoxicity of neomycin was observed and RU 25434 appeared to be relatively less toxic than amikacin. The use of new-born guinea-pigs seem to be particularly suitable for this type of study because of their apparent sensitivity to ototoxicity.

Age Factors↗

Ontogeny of neural discharge patterns in the ventral cochlear nucleus of the mongolian gerbil.

Discharge patterns were recorded extracellularly from single neurons in the ventral cochlear nucleus (VCN) of Mongolian gerbils ranging in age from 10 days after birth (DAB) to adult, a period which includes the onset of responsiveness to acoustic stimulation. At 10 DAB none of the neurons encountered within the VCN responded to acoustic stimulation. At 12 DAB approximately 15% of the neurons isolated in VCN were responsive. This coincided with the earliest cochlear microphonic potentials and preceded the appearance of the cochlear compound action potential (AP) by two days. At 14 DAB, or older, the great majority of neurons isolated in VCN responded to acoustic stimulation. Most parameters of VCN neural function exhibited significant changes between 12 and 18 DAB: neural thresholds improved approximately 100 dB; mean spontaneous discharge rate increased; the high-frequency range of characteristic frequency (CF) values increased from 10.0 to 24.0 kHz; the upper limit for phase locking increased from 0.8 kHz to 3.0 kHz; dynamic range increased from 16 dB to 44 dB, and the proportion of units with well-defined initial onset peaks in their post-stimulus-time (PST) response patterns increased from 40% to 100% of units. Most of the neural parameters examined achieved adult characteristics by 18 DAB. Frequency tuning (Q10dB) matured earlier for high-CF units. The most sharply tuned neurons with high CFs (greater than 4 kHz) at 12 DAB had Q10dB values equal to those for adults. None of the neurons with low CFs (less than 4 kHz) had Q10dB values greater than 1.2 at this age. Classical 'on' PST response patterns were not seen at 12 and 14 DAB. A unique PST response type, characterized by very long latency phasic discharge, was observed only at 12 DAB. None of the VCN neurons recorded from 12 DAB subjects displayed rhythmic 'bursting' or 'pulsing' PST response patterns, as has been reported at the earliest stages of functional development in the VCN of the cat. Most units were capable of sustained discharge, even with long stimulus durations. Units with 'primary-like' PST response patterns at 12 exhibited greater variability in first spike latency and less pronounced initial rates of firing than was characteristic in adults, resulting in poorly defined onset peaks. In contrast, units with chopper PST response patterns showed well-defined onset peaks.

Animals↗

Evoked acoustic emissions and cochlear microphonics in the mustache bat, Pteronotus parnellii.

In the echolocating bat, Pteronotus parnellii, otoacoustic responses at a frequency of 62 kHz are measurable in the external ear canal during continuous and after transient acoustic stimulation. These responses are interpreted to represent emissions from the cochlea. They can reach an amplitude as large as 70 dB SPL and occur in the frequency range most important for echolocation, namely on the average about 700 Hz above the constant frequency component of the orientation calls. A sharp maximum of the amplitude of cochlear microphonic potentials at about 62 kHz could be correlated with the emission frequency. In one bat an evoked otoacoustic response changed to a spontaneous otoacoustic emission. The frequency and amplitude of the evoked otoacoustic responses reversibly decreased after exposure for 1 min to continuous sounds of more than 85 dB SPL with frequencies of about 2.5-7.5 kHz above the emission frequency. Similar effects occurred during anaesthesia or cooling. A possible relation between the existence of otoacoustic emissions and morphological specializations of the cochlea is discussed.

Acoustic Impedance Tests↗