Biomedical subjects

P Valli

Publications and source records attributed to P Valli.

At least 19 recordsLinked to original sources

PubMed2003

Na+ currents in vestibular type I and type II hair cells of the embryo and adult chicken.

In birds, type I and type II hair cells differentiate before birth. Here we describe that chick hair cells, from the semicircular canals, begin expressing a voltage-dependent Na current (INa) from embryonic day 14 (E14) and continue to express the current up to hatching (E21). During this period, INa was present in most (31/43) type I hair cells irrespective of their position in the crista, in most type II hair cells located far from the planum semilunatum (48/63), but only occasionally in type II hair cells close to the planum semilunatum (2/35). INa activated close to -60 mV, showed fast time- and voltage-dependent activation and inactivation, and was completely, and reversibly, blocked by submicromolar concentrations of tetrodotoxin (Kd = 17 nM). One peculiar property of INa concerns its steady-state inactivation, which is complete at -60 mV (half-inactivating voltage = -96 mV). INa was found in type I and type II hair cells from the adult chicken as well, where it had similar, although possibly not identical, properties and regional distribution. Current-clamp experiments showed that INa could contribute to the voltage response provided that the cell membrane was depolarized from holding potentials more negative than -80 mV. When recruited, INa produced a significant acceleration of the cell membrane depolarization, which occasionally elicited a large rapid depolarization followed by a rapid repolarization (action-potential-like response). Possible physiological roles for INa in the embryo and adult chicken are discussed.

Animals↗

PubMed2002

Morphological changes in the frog cerebellar cortex after unilateral section of the statoacustic nerve.

To investigate a possible role of the cerebellum in vestibular compensation that follows a lesion to the vestibular apparatus, the morphological changes of the cerebellar cortex of adult frogs following unilateral statoacustic nerve section was analyzed by means of electron microscopy starting from 3 days after the neurectomy for up to 6 months. On the ipsilateral side, massive abnormality was found in all layers at early postsurgical intervals. This involved both nerve fibers and cell bodies. Fibers often appeared condensed or vacuolated with poorly compacted myelin sheath. Cells had electronlucent and vacuolated cytoplasm to varying extent. Alterations became less conspicuous after 30 days and after 60 days altered nerve cells were no longer present. On the contralateral side, only a few Purkinje and granule cells were affected at early postsurgical stages. This may derive from the fact that, in the frog, some of the vestibular primary afferents reach contralateral cerebellar cortex. At 30 days, alterations had substantially progressed, and at 60 days they involved all the cortical layers. Fiber debris was present in the granular and molecular layers and numerous Purkinje cells were electrondense and shrunken. This lateness in alteration may be a consequence of the prolonged silence of the vestibular nucleus contralateral to the lesion. At 4 and 6 months the tissue architecture was normal.

Animals↗

PubMed2002

Effect of low intensity electrical stimulation on quadriceps muscle voluntary maximal strength.

BACKGROUND: Evaluate the effect of low intensity electrical stimulation (ES) training on strength. We purposefully used a low ES stimulation intensity to have it well accepted by middle aged and low performing people. Relate strength to metabolic parameters. METHODS: Experimental design. Protocol 1: effects of 11 day low intensity ES training on quadriceps muscle maximal voluntary contraction (MVC). Protocol 2: effects of 3 day training at low intensity ES + voluntary contraction at 60% of MVC (co-contraction). VARIABLES MEASURED: maximal voluntary strength (FMAX), strength during ES (FES), strength developed during co-contraction (FES-C), oxygen consumption, heart rate. Experimental design included a basal session, a training program and controls of measured variables during and at the end of the training program. PARTICIPANTS: protocol 1: experiments were done on 13 healthy and sedentary subjects (6 males and 7 women, mean age 50.6 years). Protocol 2: experiments done on 6 healthy sedentary men (mean age 31.5 years). RESULTS: Protocol 1: FMAX increased significantly (p<0.05) to 14 and 19% at day 6 and 11, respectively. During ES, oxygen consumption increased by 20%, but no change in heart rate was observed. Protocol 2: FMAX significantly increased (about 5%) in subjects who trained with co-contraction; conversely, FMAX did not significantly increase in a control group matched for age who trained only with voluntary contractions. CONCLUSIONS: Low intensity ES in sedentary and poorly performing people increases significantly FMAX during MVC possibly via facilitatory neurogenic mechanism.

Electric Stimulation↗

PubMed2001

beta amyloid-induced disruption of ionic balance: studies on the isolated frog labyrinth.

The beta-amyloid peptide (A beta) is a key player in the pathogenesis of Alzheimer's disease. Although its mechanisms of action are not fully elucidated, a disruption of ionic homeostasis has been suggested, and A beta aggregation in fibrils seems correlated to its toxic potential. In the present work, we studied the effects of different A beta fragments on the activity of frog ampullar nerve fibers. Our results show that A beta fragments are able to reduce ampullar nerve responses, with a potency correlated to their fibrillogenic capability. This study may have clinical implications, since vestibular problems are often reported in Alzheimer patients, and provide a model for the dissection of A beta effects in a simple multicomponent system.

Action Potentials↗

PubMed2001

Regional distribution of calcium currents in frog semicircular canal hair cells.

In the present work we studied the regional expression of voltage-dependent Ca channels in hair cells from the frog semicircular canals, employing whole-cell patch-clamp on isolated and in situ hair cells. Although Ca channels are thought to play a major role in afferent transmission, up to now no data were available regarding their distribution in vestibular organs. The problem appears of interest, especially in the light of recent results showing the presence of multiple Ca current components in semicircular canal hair cells. Our data suggest the presence, in all regions of the crista ampullaris, of two classes of cells, one displaying an inactivating Ca current (R1) and one lacking it. In the former cells, Ca current amplitude decreased from the central to the peripheral zone (the maximal currents being observed in the intermediate zone). Only L-type and R2 current components displayed regional differences in expression, whereas the size and properties of R1, although variable among cells, were not regionalized. However, in cells lacking R1, Ca current amplitudes were similar regardless of cell shape and location. The possible contributions of this Ca current distribution to afferent discharge properties are discussed.

Animals↗

PubMed2001

Betahistine produces post-synaptic inhibition of the excitability of the primary afferent neurons in the vestibular endorgans.

Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the action of betahistine in the vestibular endorgans. Experiments were done in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM; n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 microM) and with the cholinergic antagonists atropine (10 microM; n = 3) and d-tubocurarine (10 microM; n = 3) were studied. The action of betahistine when co-administered with these drugs was the same as that in control experiments, indicating that its effects did not include nitric oxide production or the activation of cholinergic receptors. In contrast, 0.01-1 mM betahistine reduced the excitatory action of kainic acid (10 microM; n = 6) and quiscualic acid (1 microM; n = 13). These results indicate that the action of betahistine on the spike discharge of afferent neurons seems to be due to a post-synaptic inhibitory action on the primary afferent neuron response to the hair cell neurotransmitter.

Ambystoma↗

PubMed2001

Effects of betahistine and of its metabolites on vestibular sensory organs.

Betahistine is widely used in the treatment of peripheral and central vestibular disorders. Till now the anti-vertigo effect of the drug was though to be mainly due to an action of betahistine on inner ear or cerebral microcirculation or on some structures of the CNS, chiefly the vestibular nuclei. Vertigo, however is, in most cases, of peripheral origin but it remains unknown whether betahistine, or some of its metabolities, may directly affect the vestibular system at peripheral level. Pharmacokinetic studies have in fact demonstrated that betahistine is transformed, mainly at the hepatic level, in aminoethylpyridine (M1), hydroxyethylpyridine (M2) and, finally, in pyridylacetic acid (M3) which is excreted with the urine. All these substances are therefore present in the body fluids of subjects treated with betahistine, and thus might have pharmacological effects. The goal of the present study was to investigate whether betahistine or some of its metabolites could exert any effect on vestibular receptors. To this end, the effects of the drugs (10(-7)-10(-2) M) have been examined on frog semicircular canals, an animal model well suited for this purpose. The effects of betahistine and of its metabolites have been evaluated by recording ampullar receptor activity both at rest and during mechanical stimulation of the sensory organ. The results demonstrated that both betahistine and one of its metabolites, the aminoethylpyridine (M1), exert effects quite similar on ampullar receptors; both these substances in fact could reduce greatly ampullar receptor resting discharge but had scanty effects on mechanically-evoked responses. This observation might justify betahistine and possibly M1 anti-vertigo effects. In fact vertigo is normally due to uncontrolled changes in vestibular receptor resting discharge. It is therefore probable that any factor able to reduce vestibular receptor resting firing rate and, in consequence, its variations, may have, as final effect, an anti-vertigo action. The observation that betahistine and M1 have similar effects might be of some clinical interest. In fact, on the basis of our data, the hypothesis may be put forward that the anti-vertigo action of betahistine is at first achieved by betahistine itself and then sustained and prolonged in time by M1.

Animals↗

PubMed2001

Action mechanism of betahistine in the vestibular end organs.

Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the betahistine action mechanism at the vestibular end organs. Experiments were carried out in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM, n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with antagonists of nitric oxide sintethizing enzyme, cholinergic drugs, and excitatory amino acids were studied. Betahistine 1 mM (n = 5) was coadministered with NG-nitro-L-arginine 3 microM. The action of betahistine remained as in control experiments. Betahistine 1 mM reduced the excitatory action of carbachol (200 microM, n = 5) in a 30 +/- 3.4%. Cholinergic antagonists atropine (10 microM, n = 3) and d-tubocurarine (10 microM, n = 3) did not modify betahistine actions. Betahistine 1 mM also reduced kainic acid (10 microM, n = 4) excitatory action in 45.5 +/- 9.8%. These results corroborate that betahistine has a peripheral inhibitory action in the spike discharge of the afferent neurons in the vestibule. This action seems to involve neither NO production nor modifications in the release of acetylcholine from the efferent fibers. The inhibitory action of betahistine seems to be due to a postsynaptic binding site on the afferent neurons.

Ambystoma↗

PubMed2000

Calcium channels functional roles in the frog semicircular canal.

Different types of voltage-operated calcium channels have been described in hair cells; however, no clear functional role has been assigned to them. As a first functional characterization of vestibular calcium channels, we studied the effect of several calcium channel agonists and antagonists on whole nerve firing rate in an isolated frog semicircular canal preparation. Resting activity was affected by all dihydropyridines tested and by omegaconotoxin GVIA, whereas only nimodipine was able to reduce the mechanically evoked activity. These results indicate that nimodipine-sensitive channels play a major role in afferent transmitter release, and omega-conotoxin GVIA sensitive channels regulate the afferent firing (possibly on the postsynaptic side) but with a less important role.

Animals↗

PubMed2000

Betahistine reduces the resting firing rate of vestibular receptors in the frog.

Although betahistine is widely used in the treatment of vertigo, it remains unclear whether it directly affects the vestibular system at the peripheral level. The effects of betahistine were therefore assessed in an isolated preparation of frog semicircular canal. Betahistine was administered either in the endolymphatic or the perilymphatic fluid and the ampullar receptor potential and mass nerve discharge were recorded at rest and during mechanical stimulation. Endolymphatic administration was without effect. In contrast, perilymphatic administration resulted in a marked reduction in ampullar receptor resting discharge, although the mechanically evoked responses were only slightly affected. As vertigo is generally caused by sudden and uncontrolled changes in the resting discharge of vestibular receptors, the ability of betahistine to reduce the resting firing rate of vestibular receptors is thought to contribute to its anti-vertigo actions.

Animals↗

PubMed2000

Effects of betahistine metabolites on frog ampullar receptors.

Previous studies have demonstrated that betahistine, an histamine-like substance used widely as an anti-vertigo drug, can decrease ampullar receptor resting discharge without affecting their mechanically evoked responses. Pharmacokinetic studies have shown that this drug is transformed, mainly at the hepatic level, into aminoethylpyridine (M1), hydroxyethylpyridine (M2), then excreted with the urine as pyridylacetic acid (M3). The goal of the present study was to investigate whether betahistine metabolites are also able to affect vestibular receptor activity. Results demonstrated that, in the range tested (10(-7)-10(-2) M), M2 and M3 exerted no effect, whereas M1, at concentrations higher than 10(-6) M, was able to reduce the resting discharge of ampullar receptors without affecting the evoked responses. M1 therefore exerts effects similar to those of betahistine on ampullar receptors. This might be of some clinical interest. On the basis of our data, the hypothesis may be put forward that the anti-vertigo action of betahistine is at first achieved by betahistine itself and then sustained by M1.

Animals↗

PubMed2000

Membrane properties of chick semicircular canal hair cells in situ during embryonic development.

The electrophysiological properties of developing vestibular hair cells have been investigated in a chick crista slice preparation, from embryonic day 10 (E10) to E21 (when hatching would occur). Patch-clamp whole-cell experiments showed that different types of ion channels are sequentially expressed during development. An inward Ca(2+) current and a slow outward rectifying K(+) current (I(K(V))) are acquired first, at or before E10, followed by a rapid transient K(+) current (I(K(A))) at E12, and by a small Ca-dependent K(+) current (I(KCa)) at E14. Hair cell maturation then proceeds with the expression of hyperpolarization-activated currents: a slow I(h) appears first, around E16, followed by the fast inward rectifier I(K1) around E19. From the time of its first appearance, I(K(A)) is preferentially expressed in peripheral (zone 1) hair cells, whereas inward rectifying currents are preferentially expressed in intermediate (zone 2) and central (zone 3) hair cells. Each conductance conferred distinctive properties on hair cell voltage response. Starting from E15, some hair cells, preferentially located at the intermediate region, showed the amphora shape typical of type I hair cells. From E17 (a time when the afferent calyx is completed) these cells expressed I(K, L), the signature current of mature type I hair cells. Close to hatching, hair cell complements and regional organization of ion currents appeared similar to those reported for the mature avian crista. By the progressive acquisition of different types of inward and outward rectifying currents, hair cell repolarization after both positive- and negative-current injections is greatly strengthened and speeded up.

Analysis of Variance↗

PubMed1999

Artifactual voltage response recorded from hair cells with patch-clamp amplifiers.

Patch-clamp amplifiers (PCAs) are commonly used to characterize voltage- and current-clamp responses in the same cell. However, the cell membrane voltage response can be severely distorted by PCAs working in the current-clamp mode. Here we compare the voltage response of pigeon semicircular canal hair cells in situ, recorded with two different PCAs, and with a classic microelectrode bridge amplifier (BA). We found that the voltage response of hair cells recorded with PCAs differed significantly from that recorded with the BA. The true hair cell membrane voltage response to positive current steps was characterized by a strongly damped oscillation, whose frequency and duration depended on hair cell location in the sensory crista ampullaris.

Animals↗

PubMed1999

Caloric stimulation of ampullar receptors: a new method to produce mechanically-evoked responses in frog semicircular canals.

A microthermistor positioned close to the exposed posterior semicircular canal in isolated labyrinth preparations of the frog was used to stimulate the sensory organ. Our results indicated that, depending on the position of the heater, the induced endolymphatic convection currents may result in either excitatory or inhibitory cupular deflections and thus in a modulation of ampullar receptor resting activity. Other possible thermal-dependent mechanisms, such as a direct action of the stimulus on vestibular sensors or endolymphatic volume changes, had, in the present experimental conditions, a minor role. Caloric stimulation could therefore represent a novel method to stimulate the semicircular canals 'in situ'.

Animals↗

PubMed1999

Effects of caloric stimuli on frog ampullar receptors.

The observation that caloric nystagmus can be evoked even in microgravity conditions argues against Barany's convective theory. To justify this result, gravity-independent mechanisms (mainly endolymphatic volume changes and direct action of the temperature on vestibular sensors) are believed to contribute to caloric-induced activation of vestibular receptors. To define the importance of both gravity-dependent and gravity-independent mechanisms, the posterior semicircular canal of the frog was thermally stimulated by a microthermistor positioned close to the sensory organ. The stimulus produced a gravity-dependent transcupular pressure difference that, depending on the position of the heater, could result in either excitation or inhibition of ampullar receptor sensory discharge. When the heater was positioned on the ampulla, or when the canal rested on the horizontal plane, no responses could be evoked by thermal stimuli. These results suggest that, in our experimental conditions (DeltaT up to 1.5 degrees C), neither a thermally induced expansion of the endolymph nor a direct action of the temperature on vestibular sensors play any major role.

Ampulla of Vater↗

PubMed1998

The vestibular hair cells: post-transductional signal processing.

Hair cells in mechanosensory systems transduce mechanical stimuli into biological signals to be presented to and analyzed by the brain. Vestibular hair cells transduce stimuli primarily associated with the organism's orientation and motion in space. When examined superficially it may appear that the hair cells act as passive transducers whereby mechanical stimulation of their hair bundle results in transmitter release at their afferent synapses. In fact, hair cell functions are more complicated, and the mechanical signals are heavily processed even before being encoded in afferent nerve activity. Hair cells are different from one another in morphology, biophysics, transmitter and transmitter receptor complements, not only across different organs (as one might expect), but even in the same organ. This review focuses on hair cell morpho-physiological properties, ionic conductances, neurotransmitters/modulators and their receptors, second messengers and effectors. Special features of hair cell neurotransmission, as the synaptic body and the presence of autoreceptors and local circuits, are also discussed, as is the possibility of a differential modulation of hair cell transmitter release in the resting and mechanically-stimulated states.

Animals↗

PubMed1998

The metabotropic glutamate receptors of the vestibular organs.

This research sought to test the presence and function of metabotropic excitatory amino acid receptors (mGluR) in the frog semicircular canal (SCC). The mGluR agonist +/- 1-aminocyclopentane-trans-1,3-dicarboxylate (ACPD) produced an increase in afferent firing rates of the ampullar nerve of the intact posterior canal. This increase was not due to a stimulation of cholinergic efferent terminals or the acetylcholine (ACh) receptor, since atropine, in concentrations which blocked the response to exogenous acetylcholine, did not affect the response to ACPD. Likewise, ACPD effects were not due to stimulation of postsynaptic NMDA receptors, since the NMDA antagonist D(-)-2-amino-5-phosphonopentanoate (AP-5) did not affect the response to ACPD, reinforcing the reported selectivity of ACPD for mGluRs. When the SCC was superfused with artificial perilymph known to inhibit hair cell transmitter release (i.e. low Ca-high Mg), ACPD failed to increase afferent firing. This suggests that the receptor activated by ACPD is located on the hair cell. Pharmacological evidence suggested that the mGluRs involved in afferent facilitation belong to Group I (i.e. subtypes 1 and 5). In fact, the Group III agonist AP-4 had no effect, and the ACPD facilitatory effect was blocked by the Group I mGluR antagonists (S)-4-carboxyphenylglycine (CPG) and (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Additional pharmacological evidence supported the presence of Group I mGluRs. Interestingly, the mGluR antagonists, AIDA and 4CPG, by themselves did not affect the resting firing rates of ampullar afferents. This may suggest that the mGluRs are not involved in resting activity but perhaps only in evoked activity (as suggested in Guth et al. (1991) Hear. Res. 56, 69-78). In addition, the mRNA for the mGluR1 has been detected in hair cells of both SCC, utricle, and saccule. In summary, the evidence points to an mGluR localized to the hair cell (i.e. an autoreceptor) which may be activated to produce a positive feedback augmentation of evoked but not resting transmitter release and thus affect afferent activity.

Afferent Pathways↗

PubMed1998

Effects of betahistine on vestibular receptors of the frog.

Betahistine is widely used in the symptomatic treatment of peripheral and central vestibular disorders. However, its remains unknown whether the drug can act directly on inner ear sensory organs. To this end, the effects of betahistine (10(-7)-10(-2) M) were examined on isolated preparations of frog semicircular canal mounted in a double-celled bath which allowed drug administration both in the endolymphatic and in the perilymphatic fluid. The effects of betahistine were evaluated by recording ampullar receptor potentials and nerve firing rate both at rest and during mechanical stimulation of the isolated preparation. The results demonstrated that endolymphatic administration of betahistine had no effect, whereas its perilymphatic administration could reduce greatly ampullar receptor resting discharge but had little effect on mechanically evoked responses. This observation may explain the anti-vertigo effects of betahistine. Vertigo is normally due to uncontrolled changes in vestibular receptor resting discharge. It is therefore probable that any factor able to reduce the resting firing rate of vestibular receptors and, in consequence, its variations, may have an anti-vertigo action.

Animals↗