Biomedical subjects

C Whitworth

Publications and source records attributed to C Whitworth.

At least 37 records · Page 2Linked to original sources

PubMed1995

Combined effects of adrenalectomy and noise exposure on compound action potentials, endocochlear potentials and endolymphatic potassium concentrations.

The effects of removal of endogenous corticosteroids via bilateral adrenalectomy in combination with noise exposure (30 min at 100 dB) were determined by recording compound action potential (CAP) and endocochlear potentials (EP), and by measuring potassium concentrations (K+e) within the endolymph. Thirty-eight Long-Evans rats were divided into groups according to experimental treatments: adrenalectomy (ADX) or non-ADX and noise exposure or non-noise exposure. CAP thresholds, EP and K+e values were subjected to repeated-measures analysis of variance with group and time as factors classifying the measurements. Noise exposure resulted in significant elevations of CAP thresholds in both the ADX and non-ADX animals, but had no effect on either EP or endolymphatic K+e. Recovery was noted during all post-exposure measurement periods and was significantly faster for ADX animals. EP and K+e did not change during or after noise exposure. ADX animals showed a non-significant reduction of EP and a statistically significant increase of K+e during all measurement periods as compared to non-ADX animals.

Acoustic Stimulation↗

PubMed1994

Kinocilia in the developing stria vascularis of the rat pup.

The mammalian stria vascularis undergoes certain developmental changes in the postnatal rat. The present study was designed to examine the ultrastructure of the stria vascularis in rat pups from immediately after birth to 20 days postpartum. The cochlea were removed with the animals under xylazine (Rompun) anesthesia and were prepared for transmission electron microscopy. Each of the three cell types in the stria were found to contain kinocilia up until 12-17 days of age. The presence of kinocilia in the intermediate and basal cells has not been previously described. Findings suggest that these organelles may serve a motile and/or sensory function to assist in the maturation of cell functions, particularly ion transport, during early stages of development.

Aging↗

PubMed1994

Structure-activity studies on 2-aryl-4H-3,1-benzoxazin-4-ones.

Eight benzoxazin-4-ones related in structure to NSC 341964 (1) have been tested for cytotoxicity in two different cell systems. Two of the benzoxazin-4-ones (3 and 10) showed good cytotoxicity (ID50 = 9.9 and 8.9 microM) in P388 cells. The nitrobenzoxazin-4-one (10) caused a significant alteration in cell cycle distribution when administered to P388 cells and was an inhibitor of porcine pancreatic elastase. Structure-activity relationships are discussed.

Animals↗

PubMed1994

Identification of A1 adenosine receptors in rat cochlea coupled to inhibition of adenylyl cyclase.

A1 adenosine receptors (A1ARs) are found in a number of tissues in the body where their physiological roles have been identified. In the cochlea, neither the existence of these receptors nor a physiological role of adenosine has been described previously. Membranes prepared from rat cochlea demonstrated high affinity and saturable binding to N6-2-(4-amino-3-[125I]iodophenyl)ethyladenosine ([125I]APNEA), an A1AR agonist, with maximum binding capacity and dissociation constant values being 40.5 +/- 0.5 fmol/mg protein and 1.28 +/- 0.03 nM, respectively. Adenosine analogues competed for [125I]APNEA binding sites with a rank order of potency characteristic of these sites being the A1AR. The [125I]APNEA binding was significantly reduced by pertussis toxin, indicating coupling of these receptors with the Gi and/or Go proteins in cochlear membranes. Photoaffinity labeling of the receptor protein with the A1AR agonist N6-2-(4-azido-3[125I]iodophenyl)ethyladenosine showed specific labeling of a 36-kDa receptor protein. Activation of the A1AR with R-phenylisopropyladenosine (R-PIA) led to inhibition of forskolin-stimulated adenylyl cyclase activity. Amplification of reverse-transcribed RNA derived from cochlear tissue by polymerase chain reaction (using primers for the bovine A1AR) yielded a 770-bp product that hybridized to an A1AR cDNA probe on Southern blots. These data indicate the presence of an inhibitory receptor in the peripheral auditory system, which may play an important role in modulating auditory functions.

Adenylyl Cyclase Inhibitors↗

PubMed1993

Furosemide ototoxicity is enhanced in analbuminemic rats.

OBJECTIVE: The purpose of this study was to investigate the effect of furosemide on the endocochlear potential (EP) of Sprague-Dawley rats and rats that lack albumin in their serum (Nagase analbuminemic rats [NAR]). DESIGN: Group comparisons between analbuminemic rats and normal Sprague-Dawley rats was carried out, with statistical evaluation using the Student's t test. SETTING: Experiments were carried out in a sound-attenuated booth in a research laboratory. SUBJECTS: Young adult Sprague-Dawley and analbuminemic rats (NAR) 50 to 80 days of age were used as experimental animals. INTERVENTIONS: Subjects were anesthetized with ketamine and xylazine. Furosemide, 35 mg/kg, was injected intravenously in each of three groups: NAR rats, NAR rats pretreated with albumin and normal Sprague-Dawley rats. MAIN OUTCOME MEASURES: Endocochlear potential was measured via the round window membrane approach. Urine samples were collected with a metabolic cage, and volumes were recorded. RESULTS: Sprague-Dawley rats had a very slight EP reduction following furosemide. The NAR rats, however, were found to have an extremely large and rapid reduction of the EP one order of magnitude greater. The NAR rats pretreated with albumin had a significantly smaller reduction of EP than NAR rats not receiving albumin. However, NAR rats pretreated with albumin had a significantly greater urine output than control NAR rats. CONCLUSIONS: These findings support the hypothesis that the access of furosemide to its site of ototoxic action in the cochlea depends on the quantity of unbound furosemide in the serum.

Action Potentials↗

PubMed1993

Dose-response relationships for furosemide ototoxicity in rat.

Furosemide is an ototoxic loop diuretic which is highly bound to serum albumin. Previous studies have shown that rats deficient in albumin are more susceptible to furosemide ototoxicity than are rats with normal serum albumin concentrations. The present study was designed to compare the dose-response relationships for furosemide ototoxicity in rats with normal serum albumin concentration to rats without albumin in their serum. Young adult rats 50-80 days of age from each group were anesthetized with Rompun, and the endocochlear potential (EP) and compound action potential (CAP) thresholds were measured before and after furosemide injection. Afer a stable EP and CAP threshold were measured, each animal was injected with a single dose of furosemide through a cannula in the jugular vein. Rats with normal serum albumin had very little change in the EP or CAP threshold until the dose of furosemide was 40 mg/kg or greater. The dose-response curves for EP reduction and CAP threshold elevation then rose steeply to reach a maximum at 50 mg/kg. Albumin-deficient rats were much more sensitive to the effects of furosemide. The dose-response curves for both EP and CAP were shifted to the left. The doses resulting in half-maximal effects in the albumin-deficient rats were about half that found in the normal rats. These findings support the hypothesis that the access of furosemide to its site of ototoxic action in the cochlea depends on the quantity of unbound furosemide in the serum.

Action Potentials↗

PubMed1992

Effects of organic acids on stria vascularis ultrastructure and function in the chinchilla.

The purpose of this study was to compare the effects of several organic acids (probenecid, sodium salicylate and penicillin G) on the endocochlear potential (EP) and the ultrastructure of the stria vascularis of the chinchilla with the effects of furosemide on these parameters. Chinchillas received 50 mg/kg i.v. doses of probenecid, sodium salicylate or penicillin G, or 25 mg/kg i.v. furosemide. The EP was monitored continuously before and for 60 min afterwards. The stria vascularis was removed at 10-min intervals from animals and from 10 to 60 min after the injection of these agents. Specimens were then processed for transmission electron microscopy. Only furosemide had an effect on the EP, causing a reversible reduction. The reduction of the EP was accompanied by the appearance of edema in the intercellular spaces of the stria vascularis. No significant edema was found after probenecid, sodium salicylate or penicillin G. This was consistent with the finding that none of these latter three agents affected the endocochlear potential.

Animals↗

PubMed1992

Effects of organic acids on the edema of the stria vascularis induced by furosemide.

Furosemide is a loop diuretic which is ototoxic. Investigations have shown the stria vascularis to be the target tissue of this ototoxic drug. The purpose of the present study was to investigate the effects of furosemide on the stria vascularis in chinchillas, in controls and in animals pretreated with the above organic acids. Control animals were injected with 0.5 ml alkalinized saline followed by furosemide IV 30 min later. Experimental animals received probenecid, penicillin or sodium salicylate IV. Thirty minutes later, furosemide was injected in the same dose as in the controls. The basal turn of the stria vascularis was rapidly removed at various times from 10 to 30 min after furosemide administration and processed for transmission electron microscopy. Control animals were found to have reversible edema of the stria vascularis. Experimental animals had variable findings. Those animals pretreated with penicillin had virtually no edema of the stria vascularis at any time. Salicylate and probenecid pretreated animals had significantly less edema from one to 10 min after furosemide injection, but more edema than controls at later times. These findings suggest a discrepancy between ultrastructural pathology and functional status of the cochlea in experimental animals pretreated with probenecid or sodium salicylate followed by furosemide. On the other hand, good structure function correlations were seen in controls and in experimental animals pretreated with penicillin.

Acids↗

PubMed1992

Development of endocochlear potential and compound action potential in the rat.

The present study was designed to investigate the developmental changes of the endocochlear potential and compound action potential simultaneously from rat pups of various ages. Animals were anesthetized with ketamine/xylazine, and the endocochlear potential was measured with a glass microelectrode. At the same time, a wire electrode was placed on the round window to record the click-evoked compound action potential. The endocochlear potential was found to be very low during the first few days of postnatal life. A rapid increase in the value of the endocochlear potential was noted between eleven and thirteen days of age, and adult-like values were recorded by seventeen days of age. Compound action potential responses were recorded at thirteen days of age to high intensity clicks, followed by a progressive improvement of thresholds and reduction of latencies. The development of the endocochlear potential and compound action potential was found to be reciprocally related - as the magnitude of the endocochlear potential increased, the compound action potential threshold declined with increasing age. The development of the endocochlear potential was found to closely approximate the development of enzymatic activity of sodium, potassium-ATPase in the stria vascularis reported by Kuijpers (1974).

Action Potentials↗

PubMed1991

Comparative acute ototoxicity of loop diuretic compounds.

A microelectrode was used to measure endocochlear potentials (EP) in adult chinchillas and to study the effects of a series of loop diuretics. EP was measured before, during and for several hours after the intravenous injection of the following loop diuretics: furosemide, piretanide, bumetanide, ethacrynic acid, indacrinone stereoisomers and ozolinone. The first four loop diuretics caused a substantial dose-related reduction of EP. The (-) isomer of indacrinone was found to cause a dose-related reduction of EP to a moderate degree. The (+) isomer of indacrinone and ozolinone caused very little change of EP, even in very high doses. Findings are consistent with data on the mechanism of action of these agents in the kidney.

Acute Disease↗

PubMed1991

Development of the stria vascularis in the rat.

The rat is an altricial animal and is thus a useful model for the study of auditory development. The endocochlear potential (EP) undergoes a rapid increase in magnitude from the end of the 1st week to the beginning of the 3rd postnatal week. The purpose of this study was to examine the ultrastructure of the developing stria vascularis in the rat pup in order to correlate functional changes with structural alterations. Rat pups of various ages underwent EP measurement under Rompun anesthesia. The cochleas were rapidly removed under deep pentobarbital anesthesia. The tissues were fixed in 2.5% glutaraldehyde and postfixed in 1.5% osmium tetroxide. Thin sections were viewed and photographed using a Hitachi H7000 transmission electron microscope. A series of distinct developmental changes were observed. Intermediate and basal cells became more distinct from one another, and basal cells became more elongated. Marginal cells underwent progressive development of basolateral infoldings. These cytologic changes may signal the development of ion transport mechanisms necessary for EP development.

Animals↗

PubMed1991

Rat as a potential model for hearing loss in biotinidase deficiency.

Biotinidase deficiency is an inborn error of metabolism that is transmitted as an autosomal recessive disorder. Symptoms include hearing loss, ataxia, blindness, mental retardation, and seizures. The metabolic defect is an inability to recycle the vitamin biotin, which is an important cofactor in key enzymes. We therefore sought to develop an animal model for this disorder by inducing biotin deficiency. Rat pups were divided into control and experimental groups. Control rats were fed a normal diet whereas experimental animals were given a diet deficient in biotin. Animals from both groups underwent brain stem auditory evoked potential testing at various ages. Wave I thresholds at various ages were similar in both groups. Latencies for wave I, however, and interpeak latencies (I-IV) were prolonged in the biotin-deficient groups compared to controls. Scanning electron microscopy of the organ of Corti in biotin-deficient animals showed no significant hair cell loss. The biotin-deficient developing rat appears to acquire functional changes in the auditory brain stem. These effects may be caused by defective myelination, since biotin is important in fatty acid metabolism.

Amidohydrolases↗

PubMed1991

Ototoxicity of furosemide during development.

The rat is an altricial animal which serves as a useful model for human auditory development. The purpose of the present study was to investigate the effects of furosemide on cochlear function and the stria vascularis ultrastructure at various postnatal ages. Rat pups anesthetized with ketamine hydrochloride/xylazine hydrochloride received furosemide 35 mg/kg intravenously (IV), and the endocochlear potential and compound action potential of the eighth nerve were recorded. The stria vascularis was removed and prepared for transmission electron microscopy. Rat pups 9 to 28 days of age had a much greater reduction of endocochlear potential and elevation of the compound action potential threshold than animals older than 30 days. These physiologic changes were accompanied by edema of the stria on transmission electron microscopy only in animals at susceptible ages. These findings support the concept of a critical period of susceptibility to ototoxic drugs during development and could have important clinical implications in premature infants.

Animals↗

PubMed1990

Organic acids do not alter the cochlear effects of ethacrynic acid.

Previous studies have shown a reduction of the ototoxicity of furosemide in chinchillas pretreated with organic acid transport inhibitors. The current studies were designed to investigate whether such a protective effect could be observed in chinchillas receiving ethacrynic acid. Chinchillas weighing 400-600 g were injected with saline followed by ethacrynic acid 12.5 mg/kg i.v. (controls) or one of three organic acids (probenecid, penicillin G and or sodium salicylate) 50 mg/kg i.v., thirty minutes prior to ethacrynic acid injection (experimentals). Endocochlear potential (EP) and compound action potential of the eighth nerve (CAP) elicited by click stimuli were simultaneously monitored before and after injection in both groups. The mean change in EP and CAP findings are consistent with observations by other investigators of the actions of these loop diuretics in the isolated loop of Henle. In the latter tissues, the 'furosemide-like loop diuretics' appear to have a different mechanism of action than does ethacrynic acid. It appears from the findings of the present study that the actions of furosemide and ethacrynic acid on the cochlea are by different mechanisms as well.

Action Potentials↗

PubMed1987

Some organic acids attenuate the effects of furosemide on the endocochlear potential.

A series of organic acid transport inhibitors significantly reduced the endocochlear potential (EP) decline produced by furosemide in the chinchilla. Probenecid, sodium salicylate and penicillin G were much more effective than novobiocin, meclofenamate or diatrizoate. Inhibitors of organic base transport, choline and N-methyl nicotinamide, had no effect on the furosemide-induced drop of the EP. These findings suggest that at least part of furosemide ototoxicity may be mediated by organic acid transport.

Animals↗

PubMed1987

Ototoxicity of indacrinone is stereospecific.

Indacrinone (MK-196) is a loop diuretic which consists of a racemic mixture. The purpose of this study was to evaluate the individual enantiomers in the chinchilla model to determine whether these compounds affect auditory function and whether a difference in ototoxic potency exists. Very little change of endocochlear potential (EP) or compound action potential (CAP) was noted in animals receiving the (+)-enantiomer. On the other hand, chinchillas injected with the (-)-enantiomer were found to have a dose related reduction in both CAP and EP. These findings suggest the possibility that the diuretic receptor in the kidney and the receptor mediating ototoxicity in the cochlea, may have similar steric requirements for interacting with loop diuretics.

Animals↗

PubMed1986

An experimental study using sodium salicylate to reduce cochlear changes induced by furosemide.

Furosemide is a loop diuretic which has been found to be ototoxic in humans and experimental animals. The ototoxic effects seem to be directed primarily towards the stria vascularis, since its shrinkage and extracellular edema have been observed in correlation with electrophysiologic changes. The present study was designed to examine the interaction of sodium salicylate and furosemide on the cochlear microstructures. Chinchillas weighing 400-600 g were used in all tests performed. The endocochlear potential (EP) was monitored continuously through a microelectrode inserted through the basilar membrane. A control group of animals was injected with 0.5 ml saline intravenously (IV) 30 min before 25 mg/kg furosemide was given. The experimental group of animals was injected with 50 mg/kg sodium salicylate IV 30 min before 25 mg/kg furosemide. The control animals were found to have a mean decrease in EP of 61.1 +/- 7.0 mV. In contrast, the experimental group had very little alteration of the EP following furosemide injection (18.7 +/- 3.9 mV). These findings suggest that sodium salicylate markedly reduces the ototoxic effect of furosemide. This effect may be mediated by an alteration of local or systemic prostaglandin metabolism, or may be due to inhibition of organic acid uptake in the cochlea.

Animals↗

PubMed1986

Changes in endolymph chloride concentration following furosemide injection.

Endocochlear potential (EP) and chloride concentration in endolymph were monitored with microelectrodes in the basal turn of the cochlea of the chinchilla. After intravenous injection of furosemide (25-100 mg/kg), the EP dropped precipitously and rapidly reached its minimum value, however, the chloride activity in endolymph decreased more gradually. Possible mechanisms for this phenomenon include a reduced electrostatic attraction of chloride ions to the scala media due to a decreased EP and a reduction of passive influx of chloride into endolymph, resulting from a reduction of active inward potassium transport by furosemide.

Animals↗