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At least 19 recordsLinked to original sources
PubMed1978

4-Aminopyridine and evoked transmitter release from motor nerve endings.

1 In the presence of tetrodotoxin, electrotonic depolarization of frog motor nerve terminals causes the appearance of stimulus-graded endplate potentials. When 4-aminopyridine is added, the graded endplate potential is converted into a triggered all-or-none response resulting in giant endplate potentials of about 70 mV amplitude and 50 ms duration. The triggered endplate potentials are abolished in Ca(2+)-free saline and are blocked by Mn(2+) ions. Sr(2+) but not Ba(2+) can replace Ca(2+) in supporting transmitter release. Mg(2+) fails, even in concentrations as high as 32 mM, to affect the amplitude and the shape of the endplate potential but abolishes it when the Ca(2+) concentration is reduced to 0.2 mM.2 Despite the large amplitude of the triggered endplate potential in the presence of 4-aminopyridine and tetrodotoxin, repetitive stimulation up to 10 Hz causes only a small decline in amplitude of successive endplate potentials. However, in the presence of (+)-tubocurarine or gallamine, repetitive nerve stimulation produces a marked decline in successive endplate potential amplitude. The fall is counteracted when evoked transmitter release is reduced in the presence of 0.2 mM Ca(2+). The results suggest that in the presence of 4-aminopyridine such large amounts of transmitter are released that even during repetitive stimulation (5 to 10 Hz) endplate potentials are of maximal amplitude.3 4-Aminopyridine causes a prallel shift to the right of the dose-response curve to Mg(2+) for blockade of nerve impulse-evoked transmitter release (in the absence of tetrodotoxin). A similar parallel shift occurs in the presence of tetraethylammonium and guanidine.4 It is concluded that 4-aminopyridine increases transmitter release by enhancing the transport efficacy for Ca(2+) across the nerve terminal membrane during nerve terminal depolarization.

Aminopyridines↗
PubMed1978

Potentiation of neostigmine and pyridostigmine by 4-aminopyridine in the rat.

The interaction between 4-aminopyridine and neostigmine or pyridostigmine was studied in vivo in the rat sciatic nerve-anterior tibialis preparation using the constant infusion of pancuronium technique. The ED50 (dose of drug which produced a 50% antagonism) of neostigmine, pyridostigmine and 4-aminopyridine were 18, 49 and 440 microgram kg(-1) respectively. The addition of 100 microgram kg(-1) of 4-aminopyridine, which produced no antagonism by itself, decreased the neostigmine ED50 to 7.4 microgram kg(-1). The addition of 200 microgram kg(-1) of 4-aminopyridine, which produced a 30% antagonism by itself, decreased the ED50 of pyridostigmine to 11 microgram kg(-1). We conclude that both neostigmine and pyridostigmine interact with 4-aminopyrine synergistically.

Aminopyridines↗
PubMed1979

Analysis of the action of 4-aminopyridine during repetitive stimulation at the neuromuscular junction.

4-Aminopyridine (4-AP) increased the quantal content (m) of end-plate potentials (e.p.p.s) evoked by continual stimulation (0.2--25 Hz) in frog end-plates depressed by Mg2+. The increase in m was due to an increase in the binomial parameter n. This was interpreted to mean that 4-AP increased the number of activated release sites. In junctions blocked by d-tubocurarine, 4-AP first increased and then decreased the amplitude of e.p.p.s. elicited during a train of stimuli of increasing frequency, indicating that 4-AP increased transmitter release more than mobilization.

Aminopyridines↗
PubMed1977

Effect of 4-aminopyridine on release of noradrenaline from the perfused cat spleen by nerve stimulation.

1. 4-aminopyridine (4-AP, 1 mM) increased noradrenaline (NA) output from the perfused cat spleen at 5 Hz by about fivefold. Enhancement of NA release by 4-AP was reversible. Output of NA induced by potassium was not affected. 2. NA output was doubled at low concentrations (0.1--0.3 mM) of 4-AP, but maximal effect was obtained at 1--3 mM. At 10 mM, it induced spontaneous release of NA which was insensitive to calcium. 3. Insignificant outputs obtained at 5 Hz in 0.1 and 0.3 mM calcium-Krebs solution were markedly enhanced by 4-AP. 4-AP enhanced release at all calcium concentrations up to 5 mM, but maximum output was obtained at 2.5 mM. 4. 4-AP at pH 8.5 was more effective in enhancing NA release than at pH 7.4. 5. 4-AP increased the recovery of intra-arterially infused NA from the control 26 to 47%. 6. 4-AP did not affect release of catecholamines (CA) from the perfused cat adrenal gland by acetylcholine (ACh). 7. It is suggested that 4-AP inactivates potassium current in sympathetic nerves and prolongs the duration of the action potential, thereby allowing a greater influx of calcium ions into the neurone to enhance release of NA.

Animals↗
PubMed1977

Effects of 4-aminopyridine at the frog neuromuscular junction.

Micromolar concentrations of 4-aminopyridine (4-AP) were able to increase the amplitude of the end-plate current in frog neuromuscular junction blocked either by d-tubocurarine or by low Ca++ high Mg++ medium. The end-plate potential was also increased. These effects were reversible. The changes in the end-plate current amplitude observed after 4-AP treatment had no effect on the end-plate current time course. There was no significant difference in the resting membrane potential or mean amplitude and frequency of spontaneous miniature end-plate potentials in the presence of 4-AP. The quantal content of the end-plate potential was increased in every preparation tested and the minimal synpatic delay was lengthened in a dose-related way. 4-AP did not modify the dependence of the amplitude of the end-plate current on membrane potential. In the presence of 4-AP, the time constant of the falling phase of the end-plate current remained an exponential function of the membrane potential. The end-plate current equilibrium potential was unaffected by 4-AP. The increase in the amount of acetylcholine released by nerve impulse induced by 4-AP occurs without modification in the calcium cooperativity. The authors suggest that 4-AP, by prolonging the presynaptic action potential, could increase calcium concentration in the nerve terminal and, thus, the transmitter release.

Action Potentials↗
PubMed1975

[Changes in transmitter release at frog neuromuscular junction induced by 4-aminopyridine].

4-aminopyridine (4-AP) at micromolar concentrations, increases the end-plate potential amplitude in curarized preparations and the mean quantal content in every preparation tested, but the spontaneous release is not modified by 4-AP. These results can explain the anticurare activity observed in the wole animal or in vitro. 4-AP prolongs the falling phase of the muscle action potential without change in the muscle membrane potential.

Action Potentials↗
PubMed1977

Some antagonists of dantrolene sodium on the isolated diaphragm muscle of the rat.

The effects of a number of potential antagonists of dantrolene sodium have been studied on twitches of the isolated hemidiaphragm preparation of the rat stimulated directly at a frequency of 0-1 Hz, after complete neuromuscular block produced by tubocurarine or erabutoxin a. The substances selected as possible dantrolene antagonists were uranyl ions, thiocyanate ions, adrenaline, caffeine, quazodine, quinine, 4-aminopyridine and the calcium ionophore a23187, all of which facilitate excitation-contraction coupling in one way or another. Contracture was the main feature of the response to A23187, the increase in the tension of the dantrolene-depressed twitches being very slight. All the remaining compounds increased the amplitude of the twitches, but only 4-aminopyridine, quinine, quazodine and caffeine were capable of restoring to the control amplitude twitches that had been maximally depressed by dantrolene. OF these, 4-aminopyridine and quinine were the most potent on a molar basis.

Animals↗
PubMed1977

The facilitatory actions of aminopyridines and tetraethylammonium on neuromuscular transmission and muscle contractility in avian muscle.

The actions of 3,4-diaminopyridine, 4-aminopyridine and tetraethylammonium were studied on the chick biventer cervicis muscle preparation. All three compounds produced a greater augmentation of indirectly elicited twitches than of directly elicited twitches. The compounds did not restore transmission in OmMCa2+ solutions but rather produced contractures that were inhibited by acetylcholine receptor antagonists. The compounds restored twitch height in one-tenth normal Ca2+ solutions and induced spontaneous muscle twitching. The compounds reversed dantrolene-induced block of directly elicited twitches. Interactions between tetraethylammonium and 3,4-diaminopyridine were also studied. In indirectly stimulated preparations, the combined effects of the two compounds were more than additive at one concentration level only. In directly stimulated preparations, the effects of 3,4-diaminopyridine were greatly enhanced by tetraethylammonium pretreatment. 3,4-Diaminopyridine pretreatment produced less synergism than tetraethylammonium pretreatment. It is concluded that the actions of the aminopyridines and tetraethylammonium on transmitter release and muscle contractility are essentially similar. These actions are postulated to arise from an inhibitory action on potassium conductance and on an ability to release calcium from nerve and muscle membranes. On the basis of the interaction studies, it is suggested that the compounds possess different binding capacities for two different sites on the potassium conducting channel.

Animals↗
PubMed1979

Three types of membrane modulations during transmitter release in rat spinal cord synapses.

Protoplasmic fracture faces of vesicle attachment sites (VSA) in the presynaptic active zone of rat spinal motoneurons were classified morphologically on the basis of particle-to-membrane relationships. Intramembranous particles are absent in type 1, located around the edges of type 2 and covering the center of type 3. Application of 4-aminopyridine (4-AP), which is known to enhance transmitter release, affected strikingly the total number of VAS (P less than 0.001) but not the percentage of the three types. It is postulated that the particle-free VAS (types 1 and 2) sharing 80--85% of VAS within the active zone, are related to exocytosis. The predominance of type 3 outside the active zone and its similarity to particle-loaded indentations possibly corresponding to coated vesicle formation, suggested that type 3 may represent endocytosis.

Aminopyridines↗
PubMed1979

Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release.

We describe the design and operation of a machine that freezes biological tissues by contact with a cold metal block, which incorporates a timing circuit that stimulates frog neuromuscular junctions in the last few milliseconds before thay are frozen. We show freeze-fracture replicas of nerve terminals frozen during transmitter discharge, which display synpatic vesicles caught in the act of exocytosis. We use 4-aminopyridine (4-AP) to increase the number of transmitter quanta discharged with each nerve impulse, and show that the number of exocytotic vesicles caught by quick-freezing increases commensurately, indicating that one vesicle undergoes exocytosis for each quantum that is discharged. We perform statistical analyses on the spatial distribution of synaptic vesicle discharge sites along the "active zones" that mark the secretory regions of these nerves, and show that individual vesicles fuse with the plasma membrane independent of one another, as expected from physiological demonstrations that quanta are discharged independently. Thus, the utility of quick-freezing as a technique to capture biological processes as evanescent as synaptic transmission has been established. An appendix describes a new capacitance method to measure freezing rates, which shows that the "temporal resolution" of our quick-freezing technique is 2 ms or better.

Aminopyridines↗
PubMed1977

The effect of foreign cations, pH and pharmacological agents on the ionic permeability of an excitatory glutamate synapse.

1. Voltage clamp studies of the post-synaptic membrane of the insect neuromuscular junction have shown that normal amplitude glutamate currents could be recorded for a limited time when external Na was completely replaced by Ca, Li, ammonium, methylamine and guanidine. No change in the reversal potential of the glutamate current was observed when Na was replaced by these ions. It is suggested that the glutamate ionic channel has a similar permeability to Na and to these foreign cations, although the foreign ions cause a longer-term block of the permeability increase or receptor function. 2. Procaine, pentobarbitone, 2-4-6-triaminopyrimidine, high and low pH and low temperature reduced the synaptic ionic permeability but did not alter the ratio of the conductance increase of Na to K (delta g Na/delta gK). 4-Aminopyridine and TEA did not reduce the synaptic ionic permeability. 3. The 3. The properties of the synaptic ionic channels resemble the tight junction transepithelial ionic channels of the mammalian gall-bladder, but are very different from the Na and K non-synaptic channels of axons. It is suggested that Na and K normally pass through a single relatively large channel containing strong proton accepting acidic ligands which render the channel cation selective.

Animals↗
PubMedDate not supplied

[Freeze fracture study of vesicle attachment sites during mediator liberation in spinal motoneuron synapses].

Freeze-fractured appearances of vesicle attachement sites (VAS) in presynaptic active zone were studied in the spinal cord of 4-aminopyridine (4-AP) treated and nembutalized rats. The VAS were classified into: type 1 containing no intramembranous particles, type 2 with particles around the edge of openings, type 3 containing several particles within the VAS. The application of 4-AP, which is known to enhance transmitter release, affected strikingly the total number of VAS (p less than 0.001) but not the proportion of the three types. The predominance of type 3 outside the active zone and its similarity to particle-loaded indentations possibly corresponding to coated vesicle formation, suggested that type 3 may represent endocytosis. It is likely that the remaining two types represent exocytosis.

Aminopyridines↗
PubMed1976

Aminopyridines and sparteine as inhibitors of membrane potassium conductance: effects on Myxicola giant axons and the lobster neuromuscular junction.

The effects of the compounds 2-, 3- and 4-aminopyridine and sparteine on membrane conductance changes were examined using both voltage-clamped Myxicola axons and the lobster neuromuscular junction. In Myxicola axons, the aminopyridines very specifically inhibited the potassium conductance when applied at concentrations of 0.1 mM to 5 mM without any apparent effect of resting membrane potential. Concentrations in excess of 5 mM were needed to inhibit noticeably the sodium conductance. Potassium conductance-voltage curves were shifted in the depolarized direction along the voltage axis with no significant change in shape. There were only minor changes in the kinetics of potassium activation. In high potassium solutions, both inward and outward potassium currents were equally sensitive to the aminopyridines. Sparteine was, in general, found to be a more potent, but somewhat less specific, inhibitor of the potassium conductance. In contrast to the aminopyridines, sparteine was more effective when applied at basic pH and in addition tended to produce a noticeable degree of potassium inactivation. When applied to the lobster neuromuscular junction, 2-aminopyridine and sparteine dramatically increased the amplitude of both excitatory and inhibitory postjunctional potentials, with little or no change in resting potential, resting input conductance, reversal potential, or miniature end plate potential amplitude or frequency. Quantal content per fiber was increased by approximately a factor of 3 for the excitatory responses.

Animals↗