Aminopyridines and synaptic transmission

COMMENTARY AMINOPYRIDINES

AND SYNAPTIC

TRANSMISSION

S. THESLEFF Department of Pharmacology, University of Lund. Lund. SWEDEN Effects on synaptic transmission Cholinergic synapses Other types of synapses Mode of action Effects on muscle Clinical and other uses

Aminopyridines are compounds with a novel, unique and rather selective mode of action on the processes responsible for transmitter release at chemical synapses. The drugs are therefore of considerable interest to investigators of synaptic transmission. The aminopyridines (2-, 3- and 4-aminopyridines; AP) and the diaminopyridines (2,3,-, 2,6- and 3,4diaminopyridines; DAP) have long been known to stimulate the central nervous system, to elevate blood pressure and to exert an anti-curare action, 4-AP and 3,4-DAP being particularly active, both effective in PM-concentrations. These actions on the nervous system result from effects on the processes responsible for nerve impulse-evoked transmitter release, the amount of transmitter liberated by each nerve impulse being enormously increased by the drugs. and 3,4-diaminopyridines are 4-Aminopyridines blockers of the potassium channel in excitable tissue and this action might explain their selective effect on transmitter release evoked by action potentials, resting release being almost unaffected by the drugs. Another blocker of the potassium channel is tetraethylammonium which augments evoked transmitter release. However, it is less potent, acting in mM concentrations. Furthermore, tetraethylammonium is not as selective in its mode of action since it also is a potent blocker of nicotinic cholinergic receptors. EFFECTS ON SYNAPTIC TRANSMISSION

In vertebrate skeletal muscle 4-AP and 3,4-DAP greatly enhance the amplitude of intracellularly recorded endplate potentials (Fig. 1A). In the experiment shown, neuromuscular transmission was blocked by 25 mM magnesium ions and 4-AP and 3,4-DAP increased. as shown by the curves, the amplitude of the endplate potential in a dosedependent manner. 3,4-DAP was about ($7 times 4hhrehtiorr.\:

pyridine.

AP.

aminopyridine:

DAP.

diamino-

more potent than 4-AP. Figure 1B is a dose response curve for 4-AP showing up to a six-fold increase in endplate potential amplitude in single fibres from the rat extensor digitorum longus muscle. In this instance neuromuscular transmission was blocked by d-tubocurarine. When endplate currents, instead of potentials, are recorded it has been shown that 4-AP has no effect on the rise time nor on the decay time of the current. Neither does the drug affect the voltage sensitivity of the decay phase of the endplate current. Furthermore, 4-AP does not alter the equilibrium potential of the endplate current (MoLG~, LEMEIGNAN & LECHAT, 1977). 4-AP is devoid of anticholinesterase activity and fails to modify the amplitude and the time course of miniature endplate potentials (MOLT rtal.. 1977; LUNDH, 1978). Therefore, no evidence has been obtained indicating that the increase in endplate potential amplitude results from alterations in the postsynaptic receptor, in its ionic channels or from a delay in the enzymatic destruction of transmitter. On the contrary. experimental data suggest that the increase in endplatc potential amplitude, induced by the aminopyridines. results from a presynaptic action involving an increase in the amount of transmitter released b) each nerve impulse. Endplate currents recorded in the presence of 3,4-DAP indicate that several thousand transmitter packages are released by each nerve stimulus. compared to only about 300 packages in the absence of the drug (KATZ & MILEDI, 1979). Transmitter release from the motor nerve obeys, within certain limits, binominal statistics. An analysis of the release process in magnesium blocked preparations shows that 4-AP increases the average number of transmitter quanta (m) released by a nerve impulse by affecting the statistical parameter (n) which is believed to correspond to the store of transmitter quanta available for evoked release (MoLG~, LEMEIGNAN & LECHAT, 1979~; LUNDH, 1979). In line with this observation. electron-microscopic studies of motor nerve terminals at the moment of impulse-evoked transmitter release. show a marked increase in the number and a cluster-

1413

~ng of the synaptic vesicles at the release sites III the

potentials

terminal in the presence of 4-AP (HEUSER.19771

IY78).

The aminopyridines muscular

not only antagonize the neuru-

block produced bl curare and magnesium

1.1WIGXAY. hotuhnum

MARSHALL& HAHVE’I. 197X: MOLG~. I!CHI~AMA & Lr (MAI. 1979h) and h\

toxin

(I.~.uIxI.

LIMIER

&

THFSLFFF.

&

MAR~~A~.~..

IY78:

effects are apparent11 not

mammalian

nerve-muscle

L.(.5t)H,

prescnr

in

tLi:~t>t~.

preparations

107X)

Ions but also that produced b> aminoglqcosidc antlhlotlcs (SISW.

(DURANT

These

also

The ammopyrldines

mcrcahc the rclcasc L)I

acetylcholinc from autonomic cholmcrgic nerxcs. At concentrations

ahovc 10 ’ v the drugs induct dosc-

dcpendcnt contractions of the puillc;l-pig

ileum which

:trc blocked b! atropine and potentlated b! cwrinc

l977tr). Spontaneous

transmitter

release from motor ncrbc

tcrmmals

is. in general. not affected hg the drugs.

However.

in the frog. 4-AP

and 3,4-DAP

produce

TAN. %AlCAMOIO I%!

(!bhUI.OKl.

lSHII>A. I‘~%1

‘h’

amount of acatblcholine released III response to ncrvc stunulation

IS great11 increased in this

bursts of high frequency miniature endplate potentials

(\:l/l.

I>IJIC &

and

potcntlatec vagal inllucnces on heart rate in the S 4

the

appearance of

giant

miniature

cndplate

vi\)

FOIJXS

prcpar‘itlon

Similar)]

!()T’)

-i-AP

node preparation of the dog (YASAGISAWA, SATWI hc T.~IKA. 197X) and the stimulus

14

r

ebokcd contractions

oi

the paras\mpa’hcticall~ inncrvatcd ocsophagu\ of the

A

cluck (At.-HAHOIW.

HoI \roh

BOWMA\.

&

SA\ AU.

107X).In both instances it does not affect the sensiII~I~! of the preparation to applied qonists.

10 3,4-DAP

8

In the spleen of the cat 4-AP

4-AP

;idrcnaline

E

output following

times. but

6

has no cfTeect on

Induced h> potassium

rc\crws

-I-AP

clTcct on evoked transmitter

release

noradrenaline

ions (KIIW~AK.

PRA.~. 1977). SimilarI>. 4

(I 111~) increases nor-

ncrvc stimuli about tive KUWE~AR

&

the inhibitor)

release of guanethidinc in

this preparation (KIRPEKAK. KIHWKAK & PRAI. 197x1. In

2 ::,j

the vds deferens of the rabbit

markedI\

potentiate

the

\ponsc to transmural

stimulation

crcasc the

ol

amount

rclea.sed Spontaneous altered (JOWS. lsolatcd SC

cffluh

;Idrenalinc (L~ANIIER.

rcin-

(noradrenahne)

of Wansmitter

preparations

\pontaneous and stimulus

I

contractile

kind significantly

transmitter

GOLKO. LASZO~.

Lascular

aminopyrldincs

sustained

k

P.~Tox.

I-AI’

nol In

increases both

evoked rcleasc OC nor-

ARXER& JOHASSSON.1977) and

potcntiatcs vasoconstrictor

responses to nerve stimuli

more than to applied noradrenaline Thus.

is 1976).

(GLOWS.

197%).

11 can hc concluded that rhc aminopyridines

enhance ncrvc impulse evoked rcleasa of noradrennline in a \;irictk of tissues. At

the

plridines

lobster

neuromuscular

increase the amplitude

(glutamatcb

and

Inhibitory

Junctional potentials

,

’

o

2

4

,

L

1

I

6

10

32

64

FIG. I. (A) Increase in the quanta!

,

126W4-AP

content (m) of the endplate potential in response to increasing concentrations of 3.4-dlaminopyridine (0) and 4-aminopyridine (e). Each dose response curve was made on a different mouse phrenic nerve hemidiaphragm muscle preparation depressed by 15 mM Mg’ . at 3O‘C. Each point is the mean of 6- 7 endplates examined. (From MoLGC) et (II., 1980.) (B) Dose response curves for 4-AP showing the increase in endplate potential amplitude (in relative units) at a nerve-extensor digitorum longus muscle preparation of the rat depressed h, tl-tubocurarine at 37’C. Each value are means f S.E.M. of 4 7 endplates in different muscles. (From LKNDII.1978.)

junction

ammo-

of both rxcitator!

(;~-alniiiobutyratc)

post-

with littlc or no change in the

postsynaptic properties of the synapr.

Neither mima-

turc endplatc potential amplitude nor frequent!, alfccted. Quanta1 content of ncrvc-choked release is increased by approximatcl!

are

transmitter

ti factor of 3 for

the excitatory responses @CHAI;F. (‘Ol.M)u, C‘OL:lON & DAVIS. 19761. Sjnaptlc transmisston

in the abdominal ganglion of

the cockroach is enhanced bq +AP Both

cvokcd excitatory

postsynaptic

(5 x IO- ’ M). potentlab

and

cvokcd inhibitory postsynaptic potentials were greatly increased in amplitude although thclr duration was unaltered. Neither the resting potential nor the pobtsynaptic membrane rcsistancc wa< mt,dified. There

Ammopyridines and synaptic transmission were no changes in the equilibrium potentials of the ions involved in postsynaptic events (HUE. PELHATE. C‘ALLK. & CHAN~LET, I Y78). In the vertebrate

central nervous system 4-AP inmonosynaptic and polysynaptic reflexes (LI.MI:IGNAN.1972; 1973 ; GALINW & RUIWMIN, 197X) b! markedly facilitating transmission in excitatory as \\cll as in inhibitory pathways of the spinal cord. The drug acts by increasing postsynaptic potentials in both kind of synapses, presumably by increasing presynaptic transmitter release. since no alteration is observed in the passive electrical properties of the soma-dendritic membrane (JANKOWSKA. LUNDBERG.

creases

R~,IXNI~ & S~XO\‘A, 1977). 4-AP also accelerates

the

turnover of noradrenaline in the spinal cord. This stimulator! eft‘ect of 4-AP is dependent on nerve impulses. since no etTect is observed following an acute section of the noradrenaline nerves to the cord (A\l)l(h & LI:AKDI-I<.1979). Ultrastructurally the prey>naplic membrane of synapses in the ventral horn of the spinal cord of rats shows an increase in the incidcnce of craters and omega-shaped indentations when the animals were treated with 4-AP. The morphological c\,idencc is consistent with the electrophysiological data showing thal 4-AP facilitates the transmitter release at spinal synapses (TOKUNAGA, SANINI & ttRFR1. 1979).

It is \vcll established that calcium ions play an important role in the coupling between nerve terminal dcpolariration and transmitter release at chemical s\napses. It seemed possible that aminopyridines COLIM substitute for calcium in the release process and thercb! cnhancc transmitter release. However, as shown h! scl-era1 laboratories. the aminopyridines fail

1415

to enhance transmitter release in the absence of extracellular calcium ions (MoL& et ul., 1977: LLir;okc CJT al., 1977~). Therefore, it is unlikely that aminopyridines can replace calcium or release calcium ions from intracellular stores in the nerve terminals during evoked release. The requirement of extracellular calcium ions for release potentiation to occur suggests that the drugs enhance the influx of calcium ions during the depolarization of the nerve terminal. In line with this rcasoning. blockers of membrane permeability to calcium ions prevent the action of 4-AP (MOLGO CJItrl.. 1977: LUSIIH. 197X; 1~~6s & THESLEFF. IY7X). Ammopridines have been shown to enhance enormouslq the infux of calcium ions into nerve terminals, as shown by Fig. 2. It illustrates that, in the presence of 4-AP or 3.4-DAP. electrotonic depolarization of tetrodotoxnblocked nerve terminals causes a massive and regenerative influx of calcium ions accompanied b> the release of man! thousands of transmitter packages. The mechanism calcium

by which

influx

the aminopyridincs

is not known.

As pointed

enhance out bk KAI.I

& MILEIX (1969). such an effect could result from a blockade of potassium efflux which would enhance inward calcium currents. A prolongation of the duration of the action potential. secondary to potassium channel blockade. would leave voltage-sensiticc calcium channels open for a longer period. In addition. it is possible that the aminopyridines halt ;I direct action on the kinetics of the calcium channel (LUNIIH & THESLEFF.1977). The aminopyridines in concentrations abour equal to or somewhat higher than those observed to augment evoked transmitter release dela! the rise and reduce the size of the outward potassium current in a variety of tissues (YEH. OXFORD. WC! & NARAHASHI.

B

A TO-

4-AP _‘,

60 -

4-AP

3

50 -

0 40. 2 B so-

‘Y _‘I

,E 4 20

-‘r------

2 10 -

50 mV

_‘f----_

O-

50ms

,

0

1

1 Current

1

2

1

3

1

4

/

5

Intensity(pA)

FIG 2. (A) In the presence of tetrodotoxin (10~’ M) to block sodmm currents. electrotomc depolariratlon of frog motor nerve terminals elicit stimulus-graded endplate potentials as shown b) the records to the left. In the presence of 4-AP (130~~) the endplate potential is no longer graded but converted to a triggered response as shown by the record to the right. (From LUNDH& THESLEFF. 1977.) (B) A graphic description of an experiment similar to that in A but with 3,4-DAP. Amplitude of endplate potential before (01 and after (0) addition of 5pM of 3,4-DAP. Note that the all-or-none triggered endplate potentials reach the equilibrium potential level for the transmitter in the presence of 3,4-DAP. The mean resting membrane potential of the fibres was -81 mV. Each point is the average of 5 measurements.

(From MOL&I et al.. 1980).

1116

A

I

/’ 4-M,, 4 >’ ,, , ’ ‘I171 ,,’ _,’

6 E 4

y”

2

w

,,*’ ,,’ ’ 3.4.DAP

I

FIG. 3. Effect of changes in the extracellular pH from 7.4 to 9.0 on the quanta1 content (m) of the endplate potential in a mouse phrenic nerve hemidiaphragm preparation depressed by 20m~ Mg*+ (A), and during the action of 0.5 PM 3.4-DAP and 5 PM 4-AP in (B). The numbers in brackets refer to the number of endplates examined. (From Mow15 et ul., 1979.) 1976; MEVES & PICHON, 1977; KIRSCH & NARAHASHI, 1978). They have this property in common with tetraethylammonium. a compound also known to enhance evoked transmitter release (KOKETSU, 1958). A feature characteristic of aminopyridines is that the steady-state block of potassium channels is more complete for low depolarizations and is gradually relieved at higher depolarizations (YEH et LIP.. 1976: ULBRICHT & WAGNER, 1976). As shown by Fig. 3, both 3,4-DAP and 4-AP are more active in increasing transmitter release at pH 9 than at pH 7.4. In the absence of the aminopyridines. a pH change from 7.4 to 9 has no effect on evoked release. 3,4-DAP and 4-AP have pKa values of about 9 and therefore at pH 7.4 only about 2”< of the compounds are in their non-ionized form while at pH 9 4%50% are non-ionized. The greater potency of the compounds at pH 9 could be explained if the drugs were more active in their non-ionized form or if the drugs had to pass the nerve membrane to act intracellularly, the passage being facilitated in their nonionized form. In support of a predominantly intracellular site of action is the prolonged persistence of the drug effects on nerve terminals (LUNDH, 1978: MOLG~, LUNDH & THESLEFF, 1980). Available evidence therefore indicate that the aminopyridines exert their action on evoked transmitter release by enormously enhancing the amount of calcium ions which enter the nerve terminal during the nerve action potential. This would explain why the drugs have little, or no, effect on spontaneous transmitter release and why synapses, irrespective of type of transmitter, are similarly affected. EFFECTS ON MUSCLE In addition to enhancing excitation-secretion ling at chemical synapses the aminopyridines

Coup-

also

affect excitation--contraction coupling m muscle. in B concentration of 1 mM. or higher. 4-AP potentiateh the twitch response of single frog, to peak tension and t\; relaxation. The rate of decay and thereby the totai duration ot rht: muscle action potential are markcdl> prolonged Twitch potentiation b> 4-AP is i:&pendent of the cutraceliular calcium concentraticun indicating that 4-AP acts b! increasing the relca?c- r!f activator cticium through a prolongation of thi .tction potential (KHAN bi EI~AN. 1979). Muscle rciaxatton produc;etl b! dantrolene. which blocks the II*IC.I~Cc:t actl\ator calcium, is cffectiveiy antagomzrd hu 4-AP (t30wM.t~. KI~AU & SA\..GI.. 1977) In ventricular and papillar! hc;.iri muscle, f-.k\l” exerts a positive inotropic effect 13: +vhat appears 10 bc a mechanism similar to that in &eletal muscle. IX. a prolongation of the duration of the action potentlat (WOI.LMT;R.WOHLFAHRI & Ktlau. !iJ7ig: Y-zNAc;!sA!+‘.‘~ & TAIKA. 1970). ln smooth muscle 4-AP enhances the eicctricnl cicitabtiity of the muscle membrant~ and thz spontaneous mechanical activity (L~.AR~+K c+!ul.. tY77). These ctrects on mechanical xtivrty ot skeierai. heart and smooth muscle can all Ix xcounted for b! the observation that aminop+tin<\. i-q blocktng the repolari7ing potassium current. iuircase the duration of the action potential (MOLW. ! WY!. thereby cltusin,g ;I prolongation of the influx and thv rciease of XIIvator calcium Into the myofibrilfar qxxc.

(‘L.INICAL AND Ol-Hl,K I:SES The first clinical use of ammopprldmes was as anticurare agents. The Bulgarian scientists PASIKW. S-rotNOV & MIYXI\, (1973) reported the 11s~:01‘4-AP as a post-operative anti-curare ageen (ii-tuhocurarine (11 pancuronium) in 722 patients. Generally theq used an intravenous dose of 20 tng. but tinses as high ii:; 10mgjkg body weight were apparently used. No scrious side-effects were described I_(. LUNDH, C C‘ARLSSOK&i S. TH~SL~FF (unpublished observationsi have tried 1-AP in a dose of 2Onsg mtravenousiy as an anti-curare agent fotiowmg ~urgicdi procedures using &tubocurarine. In this clo\e. muscle strength returned upon the administration 01 3-GP. but the drug was no better than conventionally used neostigmine. In addition. 3-.4P IL~(! ;maleptic efyects which were deemed undesirable postoperatively. MILLER ct al. (1979) have used A-AP, 0.35 m&kg. in combination with neostigmine o:- pyridostigminc to antagonize pancuronium induced neuromuscular blockade. The authors conclude that 4-AP potentiates antagonism of a pancuronium-Induced neuromuscular blockade by neostigmine or pyridostigmine. Also. less atropine was needed to prevent cardiac muscarinic stimulation when 4-AP was used in combination with the anticholinesterase agent

Aminopyridines

and synaptic

In myasthenia gravis. 4-AP has been tested by repeated injections in six patients (LUNDH. NILSON & ROSI~K.. 1979). The drug caused improvement of muscle strength and neuromuscular transmission as demonstrated by clinical observations and repetitive electrical nerve stimulation. 4-AP was effective in patients without any other treatment as well as in patients undergoing treatment with anticholin&erases. It was concluded that 4-AP might be of value as a supplementar! drug in the treatment of myasthcnia gravis. 4-AP has also been used intravenously and orally in the treatment of the Eaton-Lambert myastenic syndrome (L~~KIIH. NILSSON & ROSEN, 1977h: AGOSI-ON.VAU WEI.KIXS & BROEKERT,1978). The muscle wcahnesz showed marked improvement and electrophysiological examination demonstrated restoration of function. One patient received 4-AP sulphate orally in 5 Joscs totalling more than lOOmg/day for 3 weeks. Animal experiments have shown 4-AP to be a potent and effective antagonist to the muscle paralysis caused bk botulinum toxin (LCINDH rt al.. 1977a). In the Birmingham outbreak of human botulism type E, 4-AP was administered to four patients by BALL, HOPKIMOK FARRELL, HI:TCHINSON, PAUL. WATSON, PAC;E. PARKER. EI)WARIIS. SNOW, SCOTT. LEONEGANADO. HASTINGS. GHOSH & GILBERT (1979). The drug was shown by electromyography to be effective in restoring

neuromuscular

transmission

and.

clini-

call!. to produce almost complete reversal of prripheral paralysis. However. this effect was transient and there was no detectable effect on respirator! muscles.

transmission

1417

4-AP has been given as single intravenous injections (20-X mg) to two patients with presenile dementia (GUSTAFSON. CARLSSON. HAGBERG. JOHANNESSON.RISBERG & THESLEFF, 1980). The drug produced no clinical improvement. The side effects reported with high dosages of 4-AP (1 mg/kg or more). have been convulsive phenomena. With lower dosages, a moderate rise in sq’stolic blood pressure (lG30mmHg). some decrease of cerebral blood flow (1@20”,,).anxiety. restlessness and insomnia. increased ocular sensitivity to light and perioral paresthesia. From the clinical experiences with 4-AP it appears to be a useful drug in the treatment of disorders involving defects in synaptic transmission in the peripheral and central nervous system. Chronic toxicity and pharmacokinetic data arc. however. still lacking. It is possible that 3.4-DAP might be clinically more favourable than 4-AP since, in animal experiments, it is. with the same efficacy. more potent on cholinergic transmission but apparently less convulsant (LI,CHAT. DEYSSON, LEMEIGNAN& ADOLPHE, 1968: MOI.G~ CT ul.. 1980). In addition, it might be mentioned that 4-AP has been used for more than a decade as a bird repellant in areas such as cornfields and airports. Baits. usually corn or grain containing 0.5-Y,, of 4-AP. are spread over the area. Birds ingesting the bait fly erraticall] and emit distress calls which produce a marked fright response in other members of the Rock (DE GRAZIO, BESSER.DE GINO. GC:ARI~XO & SCHAFER. I97 I I.

REFERENCES A(;OSI~~ s., VAT WFFRI)I!U P. & BROEEERTA. (1978) Effects of 4-aminopyidine in Eaton Lambert syndrome. Br. J. .I/,ue.5Y/l.50, .?Xi~?XS. AL-HABOLIBIH. A.. BOWMANW. C., HOUSTON J. & SAVAGEA. 0. (1978) Effects of 4-aminopyridine on the isolated parasympathetically innervated oesophagus of the domestic fowl chick. J. Phurm. Pharmac. 30. 517-518. AVIII:S N. E. &

L~ASIIEK

S.

(1979)

Effects of 4-aminopyridine

on the turnover

of monoamincs

in the central

nervous

51stem BALL A. R. G. ( lY79) 48.473

of the rat. J. .Vrurul Trans!n. 44. I-1 2. P., HOIXIX~N R. B.. FARRELL I. D.. HU~HIVSON J. G. P.. PAUL R.. WATSONR. D. S.. PAGEA. J. F.. PARKER F.. EIIWARIX C. W.. SNOW M.. SCOTT D. K.. LEONE-GAI\‘AIIO A.. HASTIUGS A., GHOSH A. C. & GILFI~,RT R. J. Human botulism caused by clostridium botulinum type E: The Birmingham outbreak. Q. J1 IV&. Ne\t Series. 491. BO~MAI\ W. C.. KHA\ H. H. & SAVAGEA. 0. (1977) Some antagonists of dantrolene sodium on the isolated diaphragm muscle of the rat. J. Pham. Pharmac. 29, 61&625. DI C~RAZIO J. W.. BESSERJ. F.. DE GINOT. J., GUARIKO J. L. 81 SCHAFERE. W. (1971) Use of +aminopqrldine to protect ripening corn from blackbirds. J. Wild/. Myrnt 35. 505- 509. DI.RA>.TW. N. & MARSHALL1. G. (1978) The effects of 3.4-diaminopyridine on spontaneous and evoked transmitter release at the frog neuromuscular junction. J. Pltysid.. Land. 280. 21 P. GALIVIIO .I. & RLII)O.W\. P. ( 1978) Facilitation of synaptic activity in rhe frog spmal cord produced h> J-aminopyrldine. 2’cwrawicrm~ Lt>rtcr.\ IO. 299 -304. Gl.O\F~RW E. (1978) Potentiation of vasoconstrictor responses bq 3- and 4-aminopyridine. Br. J. Phurtnuc. 63. 577 5x5. GUSTAFS~N L.. CARLSWN C., HAGBERGB., JOHANNESXIN G.. RISBERGJ. & THESLEFFS. (1980) 4-aminopyridine treatment in presenile dementia. In preparation. H~L:SERJ. E. (19771 Synaptic vesicle exocytosis revealed in quick-frozen frog neuromuscular junctions treated with J-aminopyridine and given a single electric shock. In Approudws to rhe Cdl Biology of Xrurom (eds. COxAN w. M. & Ff.RRFUI)I LLI J. A. 1 .%c. of’ .Yrurosci. .Sjwlp. 2, 2 15-239. H~IF B.. PFLHATLM.. C’ALLFC J. J. & CHANELETJ. (1978) Synaptic transmission in the sixth ganglion of the cockroach: XIIO~ of 4-aminopyridme. .I. e\-p. Bid. 65. 5 17- 527.

il.LI 5 P. & prHbSLtFtS. (lY7X)&nninopyridlne

and e\uked

transmitter

release from motor nerve end~ngi. /jr. ./. ~/~,(r,~:~~~

64. b2.i 029. JAYC;O\VSKA E.. IdI~i)B!zKC; A.. K~'lXNlk P. hi s\ KU\ A E. 11077) Ekcts 01 -&ul~inop!ridinc and Inhibitor)

synapses In the spinal cord


JOIIUS A.

transmlhsion KAV

S.

LA\IO\

m the rabbit

P. A. 6;r PAIO~

D

M. (1976) The potentiating

has Jefercna. f.trr,. .I Pi!lrI~rllu, 38, 7;

B. & MILEUI R. (1969) Spontaneous

Lonti. 203,

on trac%u%ion

in c\iltator!

E~,J~II Kt,\. 136, 3x7 792

and evoked

activity

eflects of 4-aminop;]

::!inc on ;tdrrncrgic

7h t>f motor

nerve endings in cafclum

Ringer

J

~II\,Q~,[.

689 706.

KAW B. & Mm:tx

3. I 1974j Estimates

of quantaI

CCWWI tiurirrp ‘&cmlcal

potenriarlon’

uf tran,m!tlcr

re~eabe. pr,~~ K

SOCK. R 205. 369 37s. KtlAb A. R. & t’lIhlA> K. A. P. 11979) Effect5 01 4-alninl,p!rlllirl~ skeletal mu\cie.

..I( 111p&j ,\io/. .\c,um/. 105. &Ii

KIKPEKAR M.. KIRPEKAR S. M. &

PRAT J. C. (1977)

perfused cat spleen by nerve stimulation KIKPI LAK M.. KIWI-I\AK retraeth\lammonium KIRSCH

Cj

E.. &

on rhc e\cl!ation

.I. Pl~~s~i.

EIfect of I-aminopyridine

Lmd. 272,

NARAHASHI T

(1978)

c.oupling in frog and ris!

[jr. ./. %~~rc.

on release ol XII ddrrnaime

from

thr

ncrvc rermmni\

is!

517 5X

S. M. B PRAI J. C’. (197X) Rcberaal of guanethidine and 4-aminopyridine.

contraction

35:

blockade of \ympalhc!ic

62. 75 78.

3.4-diamlnopyridine

a potent

new

potassium

channel

t

Biopkr'L,

blocker

507 511 KohI.nI1

K. (195x1 Action of rrtrarthylammoni~Ini

713 21s. L~.AIIILK S.. AKNI:R A. B JOHANSSO> 9.

I lY77)

release in the rat portal vein 1,) vitro. EW LWHA~

chloride

on nc‘uromu\cular

Effects of J-amlnop>rldinc

afferent vollc>. the monosynaptic

on mechanical

in irop\

IW .I Pli~fioi.

uctt\it\.

19.3.

,ind noradrenahne

J. Plturtrt~rc~ 46, 351 361.

P.. Dr ~SSOI G.. LI+WIG?.AN M. & AIXJLPIIL M. (196X) Toxicit?

I irr~ISourr.~) et i/t ritro (culture5 L~MI:IGNAN M. f 1972) Analysis of

transmission

cellulaires).

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1 April 19801