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Biomedical subjects

P S Guth

Publications and source records attributed to P S Guth.

At least 19 recordsLinked to original sources
PubMed1992

The inactivating potassium currents of hair cells isolated from the crista ampullaris of the frog.

1. A-type outward currents were studied in sensory hair cells isolated from the semicircular canals (SCC) of the leopard frog (Rana pipiens) with whole-cell voltage- and current-clamping techniques. 2. There appear to be two classes of A-type outward-conducting potassium channels based on steady-state, kinetic, pharmacological parameters, and reversal potential. 3. The two classes of A-type currents differ in their steady-state inactivation properties as well as in the kinetics of inactivation. The steady-state inactivation properties are such that a significant portion of the fast channels are available from near the resting potential. 4. The inactivating channels studied do not appear to be calcium dependent. 5. The A-channels in hair cells appear to subserve functions that are analogous to IA functions in neurons, that is, modulating spike latency and Q (the oscillatory damping function). The A-currents appear to temporally limit the hair cell voltage response to a current injection.

Animals↗
PubMed1991

Differential modulation of spontaneous and evoked neurotransmitter release from hair cells: some novel hypotheses.

It has been generally accepted that even in the absence of mechanical stimulation of the transductional elements, a resting depolarizing current exists which is ultimately responsible for the spontaneous release of neurotransmitter. Movement of the transductional elements modulates this resting current and thereby the evoked release of neurotransmitter occurs. Recent data from our laboratory and others have led us to question whether the relationship between spontaneous and evoked neurotransmitter release is as simple as stated. Indeed, a variety of experimental manipulations appear to influence the two modes of release differently. Examination of our results and the results of others has led us to four hypotheses: 1. the two modes of neurotransmitter release are processed differently by the hair cells; 2. cyclic AMP is involved in spontaneous but not evoked neurotransmitter release; 3. there is a positive feedback step involving an excitatory amino acid and its receptor on the hair cell in evoked neurotransmitter release and; 4. different pools of calcium are involved according to the mode of release. Accordingly, there may be several biochemical steps between the transductional movement of the stereocilia at the apex of the hair cells and the ultimate release of the neurotransmitter at the base of these cells. Some of these biochemical steps are different depending on whether the mode of release is spontaneous or evoked. These biochemical steps may amplify or at least interact with the biophysical processes previously described in the hair cells.

Acetylcholine↗
PubMed1990

Cholinergically-induced changes in outward currents in hair cells isolated from the semicircular canal of the frog.

Two cholinergically-induced modulations of membrane conductances have been identified in hair cells isolated from the crista ampullaris of the leopard frog (Rana pipiens), using the whole cell recording configuration of the patch clamp technique. Of 56 crista hair cells tested, 28 showed drug-induced changes in membrane current or membrane potential which were repeatable and could be reversed with washout of drug. The predominant effect (observed in 20 hair cells) of acetylcholine (Ach, 100 microM) to 1mM) or carbachol (1 microM to 50 microM) applied to these hair cells was the reduction of an outward current corresponding to a change in conductance of approximately -0.22 nS. This action by Ach on hair cells has been inferred from previous studies of afferent fiber discharge which reported an increase in firing rate with stimulation of efferent fibers or exogenous application of cholinomimetics (Bernard et al., 1985; Valli et al., 1986; Guth et al., 1986; Norris et al., 1988a). The Ach-induced reduction in outward current was associated with a depolarization of the zero-current membrane potential by approximately +2.5 mV. In a total of 8 hair cells, an Ach-induced reversible increase in outward current was recorded. Changes in conductance were approximately +0.13 nS and were associated with a hyperpolarization of the zero-current membrane potential by approximately -2.2 mV. This current increase is likely to be responsible for the inhibitory post-synaptic potentials (IPSPs) which have previously been recorded intracellularly from acoustico-lateralis hair cells during stimulation of the efferent innervation (Flock and Russell, 1976; Ashmore and Russell, 1982; Art et al., 1984, 1985). Of the remaining 28 hair cells, six cells failed to exhibit any change in membrane conductance or membrane potential in the presence of cholinomimetics while an additional 15 cells exhibited decreases, and 7 cells exhibited increases in outward conductance, during application of Ach or carbachol, which were neither reversible with washout nor repeatable. The Ach-induced decrease in outward current could be reversible blocked by removal of Ca2+ from the external solution. The antagonism of the Ach-induced decrease in outward current by atropine (10(-5) M) suggests that this current may correspond to a facilitatory, 'atropine-preferring' Ach receptor mediated response previously identified in the isolated semicircular canal (Norris et al., 1988a).(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1990

Evaluation of amino-oxyacetic acid as a palliative in tinnitus.

Amino-oxyacetic acid (AOAA) was evaluated as a palliative in tinnitus. Sixty-six patients with tinnitus presumed to be of cochlear origin were given either a placebo or 75 mg of AOAA four times a day for 1 week. Response was evaluated by both audiometric measurement of tinnitus loudness and subjective rating by patients of change or no change in tinnitus severity. Because loudness measurements and self-rating have not been shown to be independent, and since the aim of clinical treatment of tinnitus is the alleviation of subjective distress, greater weight was given to the patient's self-rating. A total of 21% of all patients reported a subjective decrease in tinnitus severity, usually within 3 to 4 days after the start of AOAA use. Patients with tinnitus caused by presbycusis or Meniere's disease were the most likely to respond to AOAA treatment with a reduction in tinnitus severity, whereas those with drug-induced tinnitus were the least likely to respond. Nausea and dysequilibrium were the most common side effects of AOAA use. Of the 21% of patients who responded to AOAA, 71% developed some type of side effect. Amino-oxyacetic acid produces a reduction in the severity of tinnitus in about 20% of patients; however, the incidence of side effects makes the drug unacceptable for clinical use.

Acetates↗
PubMed1989

Electrophysiological properties and morphology of hair cells isolated from the semicircular canal of the frog.

Hair cells isolated from the crista ampullaris of the frog (Rana pipiens) remained viable for up to 5 h and were studied using whole cell voltage- and current clamp recordings. Morphological characteristics of isolated crista hair cells were compared with hair cells studied in situ using light- and electron microscopy. While other labyrinthine hair cells such as mammalian inner and outer hair cells of the cochlea, saccular hair cells of the frog, and cochlear hair cells of the turtle typically have a cylindrical shape, the crista hair cells in the frog are predominantly bulbous, having a thin elongated trunk projecting from a spherical base just large enough to enclose the nucleus. This shape correlates well with the compressed packing configuration of hair cells of the crista ampullaris observed in situ in the histological material. The support cells often failed to separate adjacent hair cells, particularly the apical ends of the hair cells. Maximal cell density on the sensory epithelial ridge appears to be achieved by this arrangement. The mean resting membrane potential (Vz) of isolated crista hair cells was -44.8 mV. Cells with smooth surfaces and apparent opacity had the most negative Vz potentials. As the cells appeared to deteriorate, there was development of transparency and cell surface granulation. Such cells had more positive initial Vz values. Cells with Vz values more positive than -15 mV exhibited a distinct, contoured nucleus. Cells lacking these indicators of deterioration were characterized by input resistances of 1.9 +/- 0.31 G omega and membrane time constants of 13 +/- 2.5 ms. A large complex outwardly rectifying current was identified which was abolished by substituting Cs+ for K+ in the internal solution. The outward K+ current had two major components: a fast tetraethylammonium (TEA)-insensitive, voltage dependent I(A)-type current which showed voltage dependent inactivation; and a TEA sensitive current which had characteristics of a calcium dependent IK(Ca)-type current. Transient changes (20 ms duration) in membrane potential mimicking that which could be produced by the transduction current during cilial displacement potently modulated the I(A) current. Depolarizing current pulses of greater than 63800 pA were required to elicit membrane voltage oscillations. The resulting membrane potential offset of at least 40 mV is well beyond the magnitude of hair cell receptor potentials making it unlikely that these oscillations would play a role in enhancing frequency selectivity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

The superiority of the Goodwin procedure over the traditional procedure in measuring the loudness level of tinnitus.

The results of two procedures for measuring the loudness level of tinnitus will be presented. The traditional procedure yielded significantly smaller loudness matches, when expressed in decibel sensation level (i.e., dB SL), than did the Goodwin procedure. The Goodwin procedure is more sensitive to pharmacologically induced changes in tinnitus loudness than is the traditional procedure. The Goodwin method correlates well with changes in patient's subjective rating of tinnitus severity. The Goodwin match has a larger reliability coefficient. Nonlinear correlation also indicates that the Goodwin procedure is superior to the traditional method.

Aminooxyacetic Acid↗
PubMed1988

Histamine and related substances influence neurotransmission in the semicircular canal.

Histamine and other imidazole-containing substances were found to increase ampullar nerve afferent firing rate while both H1 and H2 histamine antagonists effectively inhibited ampullar nerve activity. A specific inhibitor of histidine decarboxylase, the enzyme which catalyses the synthesis of histamine, reduced ampullar nerve firing in a dose-dependent manner. These observations suggest a physiological role for histamine in the inner ear. Maintenance of a response to histamine after de-efferentation of the crista ampullaris supports the hypothesis that the site of action is the hair cell; antagonism of the histamine response by a cholinergic antagonist, atropine, and antagonism of a cholinergically mediated facilitation by the histaminergic antagonist pyrilamine, indicate that the site of action may involve the acetylcholine receptor complex on the crista ampullaris hair cells. The observation that imidazole-containing compounds cause significant effects on semicircular canal neurotransmission provides an important finding with regard to the site of action of antihistamines used for the treatment of vertigo and motion sickness.

Animals↗
PubMed1988

Three tests of the hypothesis that glutamate is the sensory hair cell transmitter in the frog semicircular canal.

Three series of experiments were devised to test the hypothesis that glutamate is the transmitter released by sensory hair cells of the frog semicircular canal. These three tests were: 1 - The Tolerance experiment (i.e. making the preparation tolerant to injected Glu yet still capable of responding to endogenous transmitter). 2 - The Glu Decarboxylase experiment (i.e. bathing the preparation in sufficient enzyme to prevent the effects of exogenous Glu by degrading it without affecting the response to endogenous transmitter) and; 3 - The Diltiazem experiment (i.e. using the calcium channel antagonist, diltiazem, to prevent the effect of exogenous Glu and yet not to interfere with endogenous transmitter release and action). The Tolerance and Diltiazem experiments produced results indicative of a clear dissociation between exogenous Glu and natural transmitter. The Glu decarboxylase experiment results were not so clear, producing both evidence for and against the hypothesis.

Animals↗
PubMed1987

Adenosine is a modulator of hair cell-afferent neurotransmission.

Adenosine has been implicated in neuromodulation in the central nervous system [(1985) Annu. Rev. Neurosci. 8, 103-124]. Its mechanism of action is thought to be a receptor-mediated inhibition of a transmitter release. To assess adenosine's role as a neuromodulator in the vestibular periphery, spontaneous activity of the afferent fibers in the ampullar nerve of the semicircular canal, in vitro, was used as the dependent variable. Afferent firing has been previously shown to depend on transmitter release by the hair cells [(1985) Brain Res. 330, 1-9]. Adenosine was shown to inhibit firing rate; the adenosine antagonist theophylline was shown to increase firing rate; the enzyme adenosine deaminase, which catabolizes adenosine to inosine, was shown to increase firing rate; the adenosine uptake inhibitor dipyridamole was shown to decrease firing rate; and adenosine was shown to be released from the isolated semicircular canal by electrical stimulation. All these findings are internally consistent and unreservedly support the hypothesis that adenosine has a neuromodulatory role in neurotransmission in the semicircular canal.

Adenosine↗
PubMed1985

[Pre- and post-synaptic activity of glutamate on preparations of the frog semicircular canal].

Glutamate (Glu) has at least two sites of action in the frog semicircular canal: the hair cell (presynaptic) and the primary afferent nerve fibres (postsynaptic). Glu's action on the hair cell results in an increased release of the natural transmitter which is responsible for a substantial increase in the frequency of firing in primary afferents. Glu produces a long-lasting depolarization in the afferent nerve fibres which does not by itself elicit any afferent discharge of impulses when the release of the natural transmitter is prevented. The difficulty of reconciling some of the observations made of the effects of Glu in semicircular canals with its presumed role as an afferent transmitter in this organ is discussed.

Animals↗
PubMed1985

The effect of glutamate on the frog semicircular canal.

L-glutamate (Glu) has at least two sites of action in the frog semicircular canal: the hair cell (presynaptic) and the primary afferent nerve fibres (postsynaptic). Glu's action on the hair cell results in an increased release of the natural transmitter which is responsible for a substantial increase in the frequency of firing in primary afferents. The presynaptic action of Glu is antagonized by D-alpha-aminoadipate (D alpha AA). Glu produces a long-lasting depolarization on the afferent nerve fibres which does not by itself elicit any afferent discharge of impulses when the release of the natural transmitter is prevented. Glu-induced nerve depolarization is only partially antagonized by D alpha AA. The difficulty of reconciling some of the observations made of the effects of Glu in semicircular canals with its presumed role as an afferent transmitter in this organ is discussed, but this role is not definitely rejected.

2-Aminoadipic Acid↗
PubMed1985

Amino-oxyacetic acid as a palliative in tinnitus.

Amino-oxyacetic acid, previously shown to cause a reversible loss of hearing sensitivity and a reduction in endocochlear potential, was tried as a palliative in human tinnitus. Because the drug seemed to have a cochlear site of action, patients were selected for the study if their audiograms were indicative of cochlear lesions and if there was a reduction in tinnitus following intravenous lidocaine (lidocaine positive). Ten such patients received either 50 or 75 mg of amino-oxyacetic acid four times a day orally for one week or placebo administered in a random, crossover, double-blind design. Of these ten, three reported subjective lessening of tinnitus. One of those three and two others not reporting subjective lessening of tinnitus showed a substantial improvement in speech discrimination scores while receiving amino-oxyacetic acid but not placebo. One additional patient who did not receive lidocaine also reported a subjective lessening of tinnitus. Four patients who were lidocaine negative showed neither subjective nor objective improvement in tinnitus after treatment with amino-oxyacetic acid.

Acetates↗
PubMed1979

Somatostatin along the auditory pathway.

Several structures associated with the auditory pathway have been examined by radioimmunoassay for their content of somatostatin. Of these, the medial geniculate body had the highest content, followed by the cochlear nucleus, inferior colliculus, auditory cortex and cochlea. Cochlear perilymph had no detectable somatostatin-like immunoreactivity.

Animals↗
PubMed1978

Detection of an auditory nerve--activating substance.

A substance or substances capable of increasing the firing rate of primary auditory fibers is detectable in the perilymph of frogs and guinea pigs subjected to sound stimulation. The increase in firing rate occurs in single units of the frog auditory nerve after perilymph obtained from frogs or guinea pigs during sound stimulation is infused into the frog perilymphatic sac. Perilymph collected from animals maintained in silence failed to cause an increase in firing rate of primary auditory fibers of the frog.

Animals↗
PubMed1978

The relationship between kanamycin ototoxicity and glucose transport.

The clinical utility of the aminoglycoside antibiotics is hampered by their well-known capacity to cause labyrinthine and renal damage. The mechanism by which these damages are produced is unknown. Attention was focused on the aminosugar moiety of these antibiotics by the finding of Owada (1962) which demonstrated that 3-aminoglucose is as ototoxic as its parent antibiotic, kanamycin. It is known that aminosugars compete with glucose for transport and that the sensory cells of the cochlea depend on glucose as a primary energy source. The hypothesis that grew out of these considerations was that kanamycin might be causing its ototoxicity by inhibiting glucose transport at one of several sites in the inner ear. To test this hypothesis the ototoxicity of kanamycin was determined in hyperglycemic animals. Hyperglycemia clearly and dramatically protects animals against ototoxicity as evidenced both by electrocochleographical and histological examination.

Animals↗