Biomedical subjects

C Whitworth

Publications and source records attributed to C Whitworth.

15 recordsLinked to original sources

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↗

PubMed1976

Multiple active forms of thrombin: binding to platelets and effects on platelet function.

The effect of various forms of thrombin on certain platelet functions has been investigated. Partially purified bovine thrombin which is a mixture of multiple active forms of thrombin, was chromatographed to yield molecular species termed alpha-, beta-, and gamma-thrombin, each of which has varying degrees of fibrinogen clotting and esterase activities. A direct correlation was observed between the ability of the different forms of thrombin to clot fibrinogen and to influence platelet function. In general, thrombin with high fibrinogen clotting activity was also a potent inducer of platelet aggregation and the release reaction, while those species with low clotting ability were poor inducers of aggregation and release.

Binding Sites↗

PubMedDate not supplied

Quinine reduces noxious cochlear effects of furosemide and ethacrynic acid.

Endocochlear potential (EP) and eighth nerve action potential (AP) were measured in chinchillas. We investigated the interaction of quinine with the loop diuretics furosemide and ethacrynic acid to determine whether the cochlear effects of these agents are attenuated by pretreatment with quinine. Animals were injected with either furosemide, 25 mg/kg intravenously (IV), or ethacrynic acid, 15 mg/kg IV. Control animals injected without pretreatment were found to have a large decrease in EP, with a decrease of compound action potentials (CAP) amplitude and an elevation of CAP threshold. Animals pretreated with quinine, 25 mg/kg, were found to have a significantly smaller reduction of EP and CAP amplitude following injection of either diuretic. No significant differences in urine volumes were noted between experimental and control groups. Quinine is known to cause nonspecific changes in the membranes of epithelial cells, which may cause alterations of the transport of organic anions by such tissues. Such an effect on epithelial cells in the cochlea may cause reduced uptake of loop diuretics in this organ, resulting in reduced toxicity.

Action Potentials↗

PubMedDate not supplied

Comparative ototoxicity of furosemide and piretanide.

The purpose of these studies was to compare the ototoxicity of piretanide to that of furosemide in the chinchilla. Chinchillas weighing 400 to 700 g were anesthetized with ketamine plus pentobarbital. Endocochlear potential (EP) was measured continuously by the round window approach using glass microelectrodes. Piretanide or furosemide injected through a jugular vein catheter in adults range from 10-100 mg/kg. Little or no change in EP was noted with doses below 15 mg/kg of either diuretic. The overall pattern of decline of EP was rather similar in piretanide-treated and furosemide-injected animals, and it was interesting to find that the dose-ototoxicity response curve for piretanide was similar to that for furosemide. The diuretic effect of equal ototoxic doses of either diuretic was equivalent. Both diuretics cause a decrease of endocochlear potential when applied locally to the round window membrane of the chinchilla as well as by systemic administration. These findings suggest that piretanide and furosemide have approximately the same propensity for ototoxicity.

Administration, Topical↗