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Biomedical subjects

Y Yaari

Publications and source records attributed to Y Yaari.

At least 55 records · Page 3Linked to original sources
PubMed1985

Suppression by phenytoin of convulsant-induced afterdischarges at presynaptic nerve terminals.

The mechanisms underlying the induction of afterdischarges at presynaptic nerve terminals by convulsant aminopyridines and their suppression by the anticonvulsant drug phenytoin were studied at the frog neuromuscular preparation. Addition of aminopyridine to the perfusing solution induced the appearance of afterdischarges in motor nerve fibres following their primary response to a single nerve stimulus. The afterdischarges seemed to originate at or near the nerve terminals and to propagate both antidromically and orthodromically. The latter resulted in repetitive activation of the neuromuscular synapse. Focal recordings of nerve terminal potentials suggested that aminopyridines may induce afterdischarges by slowing spike repolarization and thereby producing a prolonged depolarization of nerve terminals. Phenytoin suppressed the aminopyridine-induced afterdischarges and the resultant repetitive excitation of the postsynaptic muscle fibres. This effect of phenytoin was associated with a depression of the action potential at the motor nerve terminals but not at their parent axons. These results single the presynaptic nerve terminals as preferential sites for convulsant and anticonvulsant actions.

4-Aminopyridine↗
PubMed1985

Phenytoin suppresses spontaneous ectopic discharge in rat sciatic nerve neuromas.

Afferent fibers ending in nerve-end neuromas generate spontaneous impulse discharge which has been implicated as a cause of paraesthesias and pain following peripheral nerve injury in man. We now show in rats that the anticonvulsant drug phenytoin (PT), applied systemically or topically onto desheathed neuromas, suppresses the generation of neuroma discharge without blocking impulse conduction. The effect is dose-dependent and reversible upon drug washout. Since PT is known to provide effective pain relief in some kinds of neuralgia, the data suggest that the clinical analgesic action of PT in these conditions may, at least in part, involve a direct suppression of ectopic impulses generated in the region of the nerve damage.

Animals↗
PubMed1985

Effects of anticonvulsants on spontaneous epileptiform activity which develops in the absence of chemical synaptic transmission in hippocampal slices.

Spontaneous epileptiform activity (SEA) develops in area CA1 of hippocampal slices, when the Ca2+ concentration in the perfusate is lowered to 0.2 mM, at which level evoked chemical synaptic transmission is blocked. We investigated the effects of different anticonvulsants on this autonomous activity, in order to determine whether the antiepileptic effect can be ascribed to an influence on neuronal excitability. Carbamazepine was the most effective to block SEA at concentrations of 1-15 microM. Phenobarbital and phenytoin depressed SEA at concentrations of 25 microM. Valproate was effective at concentrations of 2-5 mM. Midazolam, a water-soluble benzo-diazepine agonist and the N-methyl-D-aspartate antagonists, DL-alpha-aminoadipic acid and 2-amino-7-phosphonoheptanoic acid were ineffective in blocking SEA suggesting that they exert their antiepileptic action by interference with synaptic mechanisms.

Animals↗
PubMed1985

On the mechanism by which phenytoin blocks post-tetanic potentiation at the frog neuromuscular junction.

Post-tetanic potentiation (PTP) was elicited at the frog sartorius and cutaneous pectoris neuromuscular junctions. A 30-sec, 30-Hz tetanus produced a 2- to 3-fold post-tetanic increase in endplate potential (EPP). In surface-recorded responses this PTP decayed in a double exponential way with time constants of 12.7 sec +/- 2.4 (SEM) and 146.8 sec +/- 36.6. In acute experiments 0.2 to 0.8 mM phenytoin (5,5-diphenylhydantoin, DPH) dramatically and reversibly reduced the early component. The late component was also reduced, although to a lesser extent and often not reversibly. DPH reduced PTP even when there was no failure of the EPP during the tetanus. Thus, the DPH effect did not require a complete block of the presynaptic action potential. At longer exposures and higher DPH concentrations EPP failures did develop, and this was associated with a more profound suppression of PTP. PTP was also elicited in tetrodotoxin (TTX)-containing solutions using electronic stimulation of nerve terminals to elicit transmitter release. This PTP had a much shorter duration (about 30 sec) than that seen in normal Ringer's solution and was followed by depression of EPP amplitudes. Thus, sodium entry into nerve terminals enables a mechanism which greatly prolongs PTP. DPH had no effect on PTP in TTX. These results, together with others in the literature, suggest that the reduction of PTP by DPH involves a graded reduction of sodium influx into nerve terminals during high rates of axon stimulation. The development of all-or-none failures of the presynaptic action potential results in even greater suppression of PTP.

Action Potentials↗
PubMed1984

Phenytoin reduces frequency potentiation of synaptic potentials at the frog neuromuscular junction.

The action of the commonly used antiepileptic drug phenytoin on frequency potentials was studied at the frog neuromuscular junction. Whereas the drug, at concentrations of 0.1-0.3 mM, had only a slight effect on EPPs evoked by nerve stimulation at a frequency of 0.5 Hz, it strongly suppressed their potentiation during tetanic nerve stimulation at 30 Hz. The post-tetanic potentiation of the EPPs was also reduced by the drug. These effects occurred without a blockade of invasion of the nerve impulse into the presynaptic terminal during the tetanus, and thus indicate a specific frequency-dependent depressant action of the drug on neurally-evoked transmitter release.

Animals↗
PubMed1983

Spontaneous epileptiform activity of CA1 hippocampal neurons in low extracellular calcium solutions.

Lowering extracellular [Ca2+] in rat hippocampal slices induces spontaneous epileptiform activity in area CA1, which is characterized by rhythmic burst firing of CA1 neurons and by prolonged negative potential shifts at the pyramidal cell body layer. This activity is accompanied by transient decreases of [Na+] and increases of [K+] in the extracellular space. In spite of the complete blockade of synaptic transmission, the wave of epileptiform activity propagates across area CA1. These findings suggest, that non-synaptic mechanisms may play a role in the generation and spread of epileptiform activity in the mammalian CNS.

Animals↗
PubMed1982

Sites of action of lead on spontaneous transmitter release from motor nerve terminals.

Lead ions have potent neurotoxic activities. At the neuromuscular junction, they depress the neurally evoked release, but strongly facilitate the spontaneous release of transmitter quanta from motor nerve terminals. The mechanisms underlying the latter action of lead were studied in the isolated frog neuromuscular preparation. The evidence presented in this article is consistent with the hypothesis that lead ions inhibit some membranal and intracellular calcium regulatory mechanisms, consequently producing an increase in the intraterminal concentration of ionized calcium, and hence, in spontaneous transmitter release.

Animals↗
PubMed1980

Post-synaptic conductance increase associated with presynaptic inhibition in cat lumbar motoneurones.

1. Motoneurones were examined in which low-intensity p.b.s.t conditioning volleys caused a 5% or greater decrease of gastrocnemius monosynaptic e.p.s.p.s without evidence of long-lasting i.p.s.p.s on superimposed single sweeps. 2. Short constant current pulses were injected into these cells and in twenty-two of twenty-three cases the voltage decay was faster when preceded by the same p.b.s.t. conditioning stimuli which caused a decrease in the Ia e.p.s.p. 3. Comparing these decays to short pulse decays generated in a simple analogue neurone model suggested that after conditioning stimuli a tonic conductance increase had occurred which was located electrotonically remote from the soma in some cases or more diffusely in other cases. 4. Long-lasting i.p.s.p.s were brought out by averaging the baseline following conditioning stimuli in ten of fifteen cases, also suggesting a post-synaptic conductance increase. 5. Averaging the voltage response to long saturating constant current pulses showed a decreased motoneurone input resistance in three of eight cases. 6. The semilogarithmic decay of four of eleven conditioned e.p.s.p.s was more rapid than controls. 7. Although short pulse voltage decay analysis revealed consistent evidence for increased post-synaptic conductance following conditioning stimuli, it was not possible to decide if the location and extent of this conductance increase were sufficient to rule out presynaptic inhibition.

Animals↗
PubMed1979

The action of chlorpromazine at an isolated cholinergic synapse.

The effects of chlorpromazine (CPZ) on cholinergic transmission were studied at the isolated neuromuscular synapse of the frog. It was found that 5 x 10(-6) M CPZ produces the following effects: (1) a reduction in end-plate potential amplitude, mainly through inhibition of transmitter release at presynaptic nerve terminals; (2) a reduction in amplitude of focally recorded end-plate current without detectable change in nerve terminal potential: (3) a decrease in amplitude of miniature end-plate potentials; and (4) an increase in the frequency of spontaneous liberation of transmitter both in normal and calcium-free Ringer's solution. It is concluded that CPZ inhibits cholinergic transmission by a complex action on presynaptic and postsynaptic elements. The relation of these findings to central cholinergic activities of CPZ is discussed.

Acetylcholine↗
PubMed1979

Phenytoin and transmitter release at the neuromuscular junction of the frog.

The effects of phenytoin (diphenylhydantoin, DPH) on transmitter release were studied at the frog neuromuscular junction. It was found that in Ringer's solutions containing a normal concentration of Ca2+ ions, DPH (1-2 X 10(-4) M) depresses neurally evoked transmitter release, whereas in Ca2+-deficient Ringer's solutions it produces an increase in evoked release. Spontaneous transmitter liberation is augmented by DPH under all the above conditions. An abrupt disappearance of the evoked response occasionally occured with stimulation at 0.5 Hz, but a normal response could be elicited by a second stimulus delivered shortly after the first. At 100-200 Hz, DPH regularly induced a partial block in synaptic transmission. In 8 mM MgCl2, this phenomenon appeared at 50 Hz and developed into a total neuromuscular blockade.

Animals↗
PubMed1978

[P material].

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Humans↗
PubMed1977

Depression of synaptic transmission by diphenylhydantoin.

Diphenylhydantoin (phenytoin, DPH) depresses synaptic transmission at the frog neuromuscular synapse by presynaptic and postsynaptic mechanisms. In normal Ringer's solution the amplitude of the neurally evoked end-plate potentials and their quantal content are reduced. Somewhat paradoxically, miniature end-plate potential (mepp) frequency is increased by the drug. These effects could result if DPH blocked both calcium transport at the axonal membrane and intracellular calcium sequestration. Mepp amplitude is reduced, and DPH also induces nerve conduction block at high rates of stimulation. The relevance of these effects to the anticonvulsive activity of DPH is discussed.

Animals↗
PubMed1973

Delayed release of transmitter at the frog neuromuscular junction.

1. After the end-plate potential (e.p.p.) there is an increase in the frequency of the miniature e.p.p.s. This delayed release of transmitter was studied at the frog neuromuscular junction, using conventional intracellular and extracellular recording techniques. E.p.p. amplitude was kept subthreshold by subnormal concentrations of activating divalent ions.2. The ratio delayed release: initial release had values between 2 and 140%, depending on the experimental conditions; it decreased with an increase in Ca concentration and quantal content.3. Delayed release is larger at low temperature than at room temperature.4. Delayed release is statistically independent of the amplitude of the preceding e.p.p.5. The time course of the decay of the delayed release is monotonic when strontium is the activating divalent ion; it shows a ;dip' in more than 50% of the cases when Ca activated release.6. The results were discussed in terms of the residual Ca ion hypothesis.

Animals↗