Search PubMed⌕ Search

Biomedical subjects

D M Quastel

Publications and source records attributed to D M Quastel.

At least 37 records · Page 2Linked to original sources
PubMed1986

Effect of a volatile anesthetic upon presynaptic excitability in mammalian hippocampus.

Changes in presynaptic terminal axon excitability produced by enflurane in the rat hippocampal slice preparation were investigated by stimulation of Schaeffer collateral terminal axons and by recording single unit antidromic action potentials. Stimulating pulses were preceded by conditioning hyperpolarizing or depolarizing current pulses. A plot of net threshold for action potential generation against the conditioning pulse yields an "accommodation curve;" changes in this curve can be used to assess the mechanism by which changes in excitability are produced. Enflurane, at a concentration equivalent to approximately equal to 1.3 times the minimum alveolar concentration, reduced excitability of terminal axons and increased accommodation in a manner consistent with a possible change in the inactivation of gNa.

Action Potentials↗
PubMed1986

The actions of dimethyl sulfoxide on neuromuscular transmission.

The effects of dimethyl sulfoxide (DMSO) on subsynaptic response and quantal release of transmitter have been studied at the mammalian neuromuscular junction. Subsynaptically, at low concentrations (up to 1% by volume), DMSO prolongs the time course of decay of miniature endplate currents, (MEPCs), with no significant effect on the amplitude of the currents, which is consistent with an action of DMSO to inhibit acetylcholinesterase. At higher concentrations of DMSO (in excess of 1% by volume) the amplitude of MEPCs and the steady state response to carbamoylcholine (carbachol) are significantly reduced, which suggests an additional action of DMSO other than pure anticholinesterase activity. After pretreatment of the preparation with a low concentration of paraoxon, higher concentrations of DMSO decrease MEPC height and cause highly variable changes in the decay time course of the MEPC. The results suggest that DMSO concentrations in excess of 1% by volume have two distinct and opposite actions on the subsynaptic response; a pure anticholinesterase activity to enhance the response and a depressant effect which is similar to that caused by d-tubocurarine. Presynaptically, DMSO increased both the spontaneous release (measured as the frequency of miniature endplate potentials, fMEPP) and the evoked release (measured as the quantal content of endplate potentials). Both types of release were increased as an exponential function, with the same slope, of the DMSO concentration, suggesting a common mode of action on these two types of release. This action appeared not to be due to an effect on the disposition or effectiveness of calcium ions inside the terminal but, rather, was due to a fusogenic or global effect. In addition, the increase in fMEPP with DMSO was the same when external calcium was replaced by barium. At the concentrations studied, up to 8% by volume, DMSO did not cause any substantial depolarization of the nerve terminal or any appreciable change in the nerve terminal action potential. In a few experiments facilitation was studied at the frog neuromuscular junction and was unchanged by DMSO at concentrations which considerably enhanced transmitter release.

Acetylcholinesterase↗
PubMed1984

Modulation of Ca2+-mediated K+-gating of erythrocyte ghosts by external Ca-EGTA.

Using 86Rb+ as a marker for K+ permeability, we find that extracellular Ca-EGTA influences the rate of 86Rb+ efflux from erythrocyte ghosts preloaded with 86Rb+ and "buffered" Ca2+. At an internal free Ca2+, where the rate of 86Rb+ efflux is minimal and uninfluenced by either external EGTA or external Ca2+, external Ca-EGTA at 0.2-0.5 mM can raise the flux rate to as high as can be attained by raising internal Ca2+, in the presence of an excess externally either of Ca2+ or of EGTA. Higher concentrations of Ca-EGTA (up to 1-2 mM) diminish the flux rate. External Ca-EDTA or Mg-EDTA can substitute for Ca-EGTA in enhancing and suppressing flux rate. The peak rate is insensitive to external free Ca2+ but depends on internal Ca2+; internal Mg-EDTA does not substitute for internal Ca-EGTA. Thus, the erythrocyte membrane is asymmetric with respect to its interaction with Ca2+ and Ca-EGTA. Also, 22Na+ does not substitute for 86Rb+. The peak rate of 86Rb+ flux produced by external Ca-EGTA is diminished by chlorpromazine (0.1 mM) and augmented by 1-propranolol (25 microM), in the same way as the rate produced by increasing internal Ca2+. The results suggest that external Ca-EGTA enhances the affinity of internal Ca2+ for its receptor(s) which operate the K+-gate at the inner surface of the membrane. At external concentrations of Ca-EGTA above 1-2 mM, 86Rb+ flux rate again rises with increase of Ca-EGTA. This phenomenon does not depend upon internal Ca2+, is not affected by chlorpromazine or by 1-propranolol, and is associated with an enhanced permeability to 22Na+, inulin, and haemoglobin.

Calcium↗
PubMed1984

The time course of miniature endplate currents and its modification by receptor blockade and ethanol.

Miniature endplate currents (MEPCs) recorded from mouse diaphragms with a point voltage clamp, without inhibition of acetylcholinesterase (AChE) and in the absence of any drug, showed in their decay phase consistent deviations from an exponential time course, consisting of (a) "curvature," a progressive increase of decay rate during most of the decay phase, followed by (b) "late" tails. Both phenomena persisted when MEPCs (and channel lifetime) were prolonged by ethanol. Curvature was increased by muscle fiber depolarization and decreased by hyperpolarization. Receptor blockade by (+)-tubocurarine, alpha-bungarotoxin, hexamethonium, or myasthenic IgG accelerated the decay of the main part of MEPCs and eliminated curvature; the time constant of MEPCs became close to the channel time constant. We conclude that curvature arises from repeated action of ACh with cooperativity in ACh-receptor interaction; the voltage sensitivity of curvature follows from the voltage sensitivity of channel closing. Ethanol, in addition to its effect to prolong channel lifetime, enhances the tendency of ACh to act more than once to open channels before being lost to the system. Analysis of the rising phase of the MEPC, in terms of driving functions, also indicated that ethanol promotes channel opening by ACh; this action can account for a substantial increase of MEPC height by ethanol when MEPCs are made small by receptor blockade. Driving functions were also voltage sensitive, in a manner indicating acceleration of channel opening, but reduction of channel conductance, with hyperpolarization. Poisoning or inhibition of AChE prolonged MEPCs without altering the duration of ionic channels. Since ethanol caused further prolongation of MEPCs after poisoning of AChE, with little change in MEPC height, we conclude that the extension of mean channel lifetime by ethanol is accompanied by a similar extension of ACh binding to receptors. After poisoning of AChE, MEPCs became very variable in time course and the decay rate (tau-1) was correlated with MEPC height with a slope of log tau vs. log height of 0.77 for MEPCs of greater than 60% mean size. This slope is larger than expected from cooperativity in ACh-receptor interaction. Correlation of tau and height of MEPCs also exists when AChE is intact; the slope of log tau vs. log height was 0.12 with or without prolongation of MEPCs by ethanol.

Acetylcholine↗
PubMed1984

Thermodynamic parameters of end-plate channel blockade.

The reaction kinetics for drug blockade of postsynaptic channels at the mouse neuromuscular junction were studied. The activation energies associated with the onward and off-rate constants, from a sequential model, were measured for procaine, scopolamine, octanol, and heptanol, and from these the transition state thermodynamic parameters of free energy (delta G++), enthalpy (delta H++), and entropy (delta S++) of activation were determined. All agents showed positive entropies of activation for the channel blocking rate constant kappa 2, with the values for the alcohols significantly greater than those for the two positively charged local anesthetics. No significant differences in the activation energies for the off-rate constant kappa-2 were observed between any of the agents. The magnitude of kappa-2 decreased as the hydrophobicity of the agent increased. The large activation energies measured for kappa 2 and kappa-2 (in excess of 10 kcal/mol) are higher than expected for simple rate-limiting diffusion, and the possibility exists that channel blockade involves conformational changes in a protein segment, induced by a hydrophobic interaction between agent and intrachannel site or sites. The large entropy increase observed in the blocking step is indicative of the agent replacing structured waters of hydration near a hydrophobic region of a protein.

1-Octanol↗
PubMed1983

Postsynaptic effects of magnesium and calcium at the mouse neuromuscular junction.

The effects of elevated magnesium and calcium concentrations on height and time course of miniature endplate currents (MEPCs) at the mouse neuromuscular junction were studied. With both ions, MEPC height was decreased; the rate of decay of MEPCs was reduced in high magnesium and was unchanged in high calcium. Raised Mg2+ or Ca2+ both acted to modify the effects on MEPC time course of procaine, scopolamine, atropine, lidocaine, and quinidine, all of which act to cause biphasic decay of MEPCs in a manner consistent with reversible "plugging" of endplate channels, with rate constants for blocking and unblocking that are sensitive to postsynaptic transmembrane potential. Both the blocking and unblocking rate constants were decreased by increasing divalent ion concentration. No such reduction of rate constants was observed using menthol or pentobarbital, which appear to block channels in a voltage-independent manner. It is concluded that the divalent ions act to alter the channel environment via interactions with charged groups in or near the endplate channels.

Anesthetics, Local↗
PubMed1983

Receptor blockade and synaptic function.

When a neurotransmitter substance is released into a synaptic cleft it acts upon subsynaptic receptors to induce a response of the target cell and also interacts with systems which act to remove the substance. At no time is there an equilibrium, and it is inappropriate to apply equilibrium kinetics to predict the consequences of modifying the system, e.g. by blocking receptors. A mathematical model predicts that the subsynaptic response to each package or "quantum" of transmitter may be insensitive to competitive receptor blockade, or to quite large changes in receptor density, provided the density of receptors is normally enough for efficient capture of transmitter. This prediction is borne out by experimental data from the voltage-clamped mouse neuromuscular junction; it requires blockade or removal of about 80% of receptors (90% after poisoning of acetylcholinesterase) to reduce the miniature end-plate current, i.e. the action of a quantum if nerve-released acetylcholine (ACh), by 50%. On the other hand, drugs that interfere with receptor function without preventing ACh binding to receptors can be just as (or more) effective in blocking nerve-applied as in blocking exogenously applied transmitter substances. At the neuromuscular junction this is seen with receptor desensitization, and "non-specific" agents such as local and general anaesthetics. We conclude that care must be taken in extrapolating from data re receptor number and/or occupancy by blocking drugs to consequences in terms of synaptic function.

Acetylcholine↗
PubMed1982

Fast desensitization of the nicotinic receptor at the mouse neuromuscular junction.

1 When low concentrations of carbachol (2-20 muM) were applied by local superfusion to mouse diaphragm endplates, there occurred a rapid decrease (within seconds) in the height of miniature endplate currents (m.e.p.cs) in addition to the increase of muscle membrane conductance.2 With 2, 5, 10 and 20 muM carbachol, m.e.p.c. heights were diminished by 5, 10, 30 and 50% respectively. A subsequent slow decrease in height took place at a rate corresponding to that reported for the slow desensitization produced by bath-applied carbachol (see Adams, 1975).3 The effect of carbachol on m.e.p.c. height was not affected by poisoning of acetylcholinesterase (AChE). After poisoning of AChE, 4 muM acetylcholine (ACh) depressed m.e.p.c. height by 23%.4 At 20 muM carbachol, both the onset and offset of the effect on m.e.p.c. height lagged behind the subsynaptic conductance change, and the calculated change of subsynaptic agonist concentration, by about 3 s; the onset rate was at least ten times faster than expected for slow desensitization.5 When the conductance responses produced by carbachol were corrected for fast desensitization, the slope of the log-response log-dose line (Hill coefficient) was increased from 1.7 to 2.0.6 The Hill coefficient for fast desensitization was 1.4. The data were compatible with a cyclic model for fast desensitization, with receptor activation not a prerequisite for desensitization of receptors.7 The failure of AChE poisoning to affect m.e.p.c. height during desensitization suggests that desensitized receptor associated with exogenous agonist can continue to bind quantal ACh.

Acetylcholine↗
PubMed1982

Modification of dose-response curves by effector blockade and uncompetitive antagonism.

Kinetic equations were derived for simple models of agonist-antagonist-receptor interaction and used to predict theoretical dose-response curves for the situation where there exists "receptor reserve" and a simple rectangular hyperbolic relation between tissue response and receptor occupancy by agonist, generated by an "effector chain" that links final response to receptor activation. Drug action within this chain, or an "uncompetitive" antagonism exerted by a reversible agonist that combines primarily with the active agonist-receptor complex, may give the appearance of classical noncompetitive or competitive antagonism, depending upon the amount of receptor reserve and upon the rate constants involved in both agonist-receptor and antagonist-receptor interaction. The apparent potency and nature of antagonism by such an uncompetitive antagonist may depend upon the particular agonist against which it is tested. The phenomenon whereby true competitive antagonists reduce the maximal response to a partial agonist can be explained if the partial agonist, in addition to activating receptors, also acts as an uncompetitive antagonist.

Binding, Competitive↗
PubMed1981

Relation between subsynaptic receptor blockade and response to quantal transmitter at the mouse neuromuscular junction.

When a quantum of transmitter is released into a synaptic cleft, the magnitude of the subsynaptic response depends upon how much transmitter becomes bound to receptors. Theoretical considerations lead to the conclusion that if receptor density is normally high enough that most of the quantal transmitter is captured, subsynaptic quantal responses may be insensitive to receptor blockade. The effectiveness of receptor blockers in depressing the subsynaptic response should be diminished by interference with processes that normally dispose of transmitter, but increased if receptor density is reduced. In conformity with equations derived from a simple mathematical model, the apparent potency of (+)-tubocurarine (dTC) to depress the peak height of miniature end-plate currents (MEPCs) in mouse diaphragm was substantially reduced by poisoning of acetylcholinesterase (AChE) and increased by partial blockade of receptors by immunoglobulin G from patients with myasthenia gravis or alpha-bungarotoxin. We calculated from the data that normally capture of quantal acetylcholine (ACh) by receptors is approximately 75% of what it would be if there were no loss of ACh by hydrolysis or diffusion of ACh form the synaptic cleft. This fraction is increased to approximately 90% by poisoning of AChE. Conversely, it normally requires blockade of approximately 80% of receptors-and after AChE poisoning, approximately 90% of receptors-to reduce ACh capture (and MEPC height) by 50%. The apparent potency of dTC to alter MEPC time-course (after AChE poisoning) and to depress responses to superperfused carbachol was much greater than its apparent potency to depress MEPC height, but corresponded closely with the potency of dTC to block receptors as calculated from the action of dTC on MEPC height. These results indicate that the amplitude of the response to nerve-applied acetylcholine does not give a direct measure of receptor blockade; it is, in general, to be expected that an alteration of subsynaptic receptor density may not be equally manifest in responses to exogenous and endogenous neurotransmitter.

Mathematics↗
PubMed1980

Steroid anaesthetics: inhibition of depolarization-secretion coupling at the mouse motor nerve terminal.

The coupling between nerve terminal depolarization and quantal secretion of acetylcholine at the mouse neuromuscular junction was estimated by measuring the multiplication of the frequency of miniature end-plate potentials (m.e.p.p.s) produced by increasing the concentration of calcium in the medium from 0.1 to 1.0 mM in the presence of 15 mM potassium. Depolarization-secretion coupling was inhibited by the anaesthetic steroids progesterone, pregnanedione, and alphaxalone. The nonanaesthetic steroid delta 16-alphaxalone also inhibited depolarization-secretion coupling with the same potency as alphaxalone. This results indicates that inhibition of depolarization-secretion coupling in nerve terminals is unlikely to play a major role in the production of anaesthesia.

Anesthetics↗
PubMed1978

A voltage-clamp study of the permeability change induced by quanta of transmitter at the mouse end-plate.

1. Miniature end-plate currents (m.e.p.c.s) were recorded from mouse diaphragm using a point voltage-clamp. The relation between m.e.p.c. amplitude and membrane potential was determined in bathing solutions of varied composition. 2. In solution containing normal sodium the relation between m.e.p.c. height and membrane potential (Im.e.p.c./Vm relation) was always linear, at least in the range +30 to -100 mV; the reversal potential (Vr) at which Im.e.p.c. was zero was close to 0. The slope of the Im.e.p.c./Vm line varied little between junctions (coefficient of variation about 20%) and was about 50 nS, or 1nA per 20 mV. The Im.e.p.c./Vm relation was not altered by withdrawal of Ca2+, addition of ethanol, or substitution of NO-3 or SO2-(4) for Cl-. 3. Alteration of K+ concentration in the bathing medium, in the range 10 to 1 mM, had no apparent effect on the Im.e.p.c./Vm relation. 4. Reduction of Na+ concentration, with isosmotic substitution of sucrose, caused rapid alteration of the Im.e.p.c./Vm relation, which became rectifying, with a slope at negative Vm less than at positive Vm. Vr was shifted in the negative direction. Quantitatively these changes were close to those predicted by the Goldman-Hodgkin-Katz formulation for permeation of monovalent ions through a membrane with constant field. 5. In solution with low Na+ (2 mM) and partial substitution of K+ for Na+, the Im.e.p.c./Vm relation was indistinguishable from that in solutions with Na" as the predominant extracellular cation. With complete substitution of K+ for Na+ the Im.e.p.c./Vm relation was a little less steep (at negative Vm) than in Na+ solution and Vr was shifted slightly in the negative direction. 6. With substitution of NH+4 for Na+, the Im.e.p.c./Vm relation was little changed (about 10% steeper at negative Vm). With substitution of Li+ for Na+, the Im.e.p.c./Vm relation remained linear, but was made less steep, at positive as well as negative Vm, and Vr was shifted slightly in the positive direction. 7. These results indicate that the permeability change associated with generation of the m.e.p.c. (i.e., evoked by a quantum of transmitter) corresponds to the opening of a single species of membrane channel that allows the free movement of K+, Na+, NH+4, AND Li+ ions along their electrochemical gradients. The channel discriminates little between these ions. The apparent order of permeability is Li+ greater than NH+4 greater than Na+ greater than or equal to K+. The apparent permeability per channel corresponds to that expected for channels of about 6.4 A diameter, 100 A length, and ionic mobility the same as in dilute solution.

Animals↗
PubMed1976

Action of amino acids and convulsants on cerebellar spontaneous action potentials in vitro: effects of deprivation of C1-, K+ of Na+.

(1) The inhibition of spontaneous action potentials in guinea pig cerebellar cortex slices by GABA, glycine, taurine and beta-alanine is maintained when C1- in the superfusion medium is almost completely replaced by NO3- or I-('permeant' anion), but the inhibition decreases in magnitude with repeated application of the amino acid. Replacement of C1- by sulfate or isethionate ('impermeant' anion) causes a conversion of inhibition by these amino acids to excitation. The initial excitation which is sometimes seen with these inhibitory amino acids in high C1- media is abolished when C1- is replaced by either permeant or impermeant anions. (2) Reduction of K+ in the medium causes an increase of inhibition by the inhibitory amino acids in the presence of high C1- and reduction of excitation when C1- is replaced by impermeant anion. (3) Excitation by GABA in impermeant anion (low C1-) media is unaffected by reduction of Na+ in the media by 50% but excitations by glycine, taurine, beta-alanine and L-glutamate are greatly reduced. (4). Excitation by GABA in impermeant anion (low C1-) media is abolished by picrotoxin and bicuculline which both suppress inhibition by GABA in a high C1- medium. Strychnine suppresses the effects of glycine, taurine and beta-alanine in either a low or high C1- medium. Bicuculline blocks the inhibitory effect of these three amino acids in a high C1- medium but does not affect their excitatory effects in a low C1- medium. (5) These results are consistent with the hypothesis that the inhibitory amino acids, GABA, glycine, taurine and beta-alanine, cause inhibition via increase of C1- (and perhaps K+) permeability and that glycine, taurine and beta-alanine also interact with strychnine-sensitive receptors mediating (perhaps indirectly) increased permeability to Na+ and, therefore, excitation in low C1- media.

Action Potentials↗
PubMed1973

Transmitter release by mammalian motor nerve terminals in response to focal polarization.

1. A method is described by which mammalian motor nerve terminals may be uniformly polarized by focally applied current, and the extra-cellular potential in the synaptic cleft, corresponding to any current, estimated.2. The relationship between log m.e.p.p. frequency and local extra-cellular field is flat for hyperpolarization and ascends linearly with depolarization. With depolarization, m.e.p.p. frequency is multiplied about tenfold for every - 18 mV. This characteristic becomes steeper the closer the polarizing electrode to the nerve terminal with a limiting value of ten-fold per - 15 mV.3. There exists a population of small m.e.p.p.s which are generated at the same end-plate as normal m.e.p.p.s.4. Following a prolonged depolarizing pulse there is an increase of m.e.p.p. frequency which continues for periods of up to several minutes.5. With hyperpolarizing pulses m.e.p.p. frequency may increase in a characteristic ;bursty' manner. Similar bursts of m.e.p.p.s also occur spontaneously, but far less frequently, without polarization.6. During a depolarizing pulse, m.e.p.p. frequency becomes maximal or near maximal within 2 sec. There is little subsequent alteration of m.e.p.p. frequency. Numbers of m.e.p.p.s occurring during depolarizing pulses follow the Poisson distribution.7. Following a depolarizing pulse, numbers of m.e.p.p.s released by a subsequent pulse may be either increased or diminished.8. Comparison of the response of m.e.p.p. frequency to raised [K] and to extrinsic presynaptic polarization leads to the conclusion that the presynaptic transmembrane potential change corresponding to any focal current pulse is about two thirds of the local extracellular potential field. Hence the slope of the linear portion of the presynaptic transfer function is about tenfold per 10 mV presynaptic depolarization.

Animals↗
PubMed1973

Cumulative and persistent effects of nerve terminal depolarization on transmitter release.

1. Following focal depolarization of rat motor nerve terminals there could often be observed an ;after-discharge' of m.e.p.p.s with transient frequencies of up to 1000/sec. This after-discharge was graded with intensity and duration of the previous depolarization.2. Following pulses which were relatively short (about 1 sec) and not too large (< -100 mV local extracellular potential field) the logarithm of m.e.p.p. frequency fell exponentially. With larger or longer pulses there was a tail to the after-discharge which could persist for several minutes.3. M.e.p.p. frequency during an after-discharge was not inhibited appreciably by nerve terminal hyperpolarization, raised [Ca] (8 mM) or lowered pH.4. Measured as a multiplication of spontaneous m.e.p.p. frequency after-discharge was depressed in solution containing no Ca(2+) and added 1 mM-MgEDTA but equal in 0.125 mM-Ca(2+) or 2 mM-Sr(2+) to that in 2 mM-Ca(2+) or 8 mM-Ca(2+).5. During an after-discharge the multiplication of m.e.p.p. frequency by focal nerve terminal depolarization or raised K(+) was reduced. This phenomenon was termed ;uncoupling'.6. It was concluded that the after-discharge is not caused by a persistent rise of K(+) concentration in the synaptic cleft, nor by a maintained nerve terminal depolarization.7. In preparations depolarized by raised K(+) m.e.p.p. frequency during a relatively small focal depolarizing pulse rose continuously, after an initial rapid rise, and after the pulse there was a tail of increased m.e.p.p. frequency. The magnitude of the rise during the pulse and the tail after it were similar on, a logarithmic basis; during both processes the logarithm of m.e.p.p. frequency usually followed (approximately) an exponential time course.8. The relative magnitude of the slow effect of depolarization, as compared with the fast effect, was increased by lowering [Ca] or increasing [Mg], and the slow effect of depolarization in contrast to the fast effect was found to exist in the presence of Ca reduced to about 10(-7)M, but only during pulses. At this [Ca] there was no rapid response to depolarization. At [Ca] about 10(-10)M, there was no response at all of m.e.p.p. frequency to nerve terminal depolarization.9. The results are discussed, and compared with similar data referring to ;facilitation' and ;post-tetanic potentiation'. It is concluded that these and the slow effect of depolarization represent the same phenomenon, a response of the transmitter release system which can be distinguished from the fast response in terms of ionic requirement as well as time course.

Animals↗
PubMed1973

The specific effect of potassium on transmitter release by motor nerve terminals and its inhibition by calcium.

1. There exist two distinct effects of potassium on the transmitter release system, one which develops rapidly and another which becomes maximal much more slowly. The fast effect is inhibited by raised Ca(2+), which does not inhibit transmitter release evoked by depolarizing pulses. Thus the fast effect is not secondary to nerve terminal depolarization.2. The fast effect of K(+) was found to consist in an increase in the slope of the linear relation between log m.e.p.p. frequency and nerve terminal depolarization. This effect is complete within a few seconds, is inhibited by raised Ca(2+), and is not produced by prolonged focal or electrotonic depolarization, which instead tends to reduce the slope of log m.e.p.p. frequency vs. depolarization.3. A slope change effect like that of K(+) was not found with ouabain or ethanol, nor did these agents depress the slope change effect of K(+). The specific action of K(+) was not exerted on release evoked in the absence of Ca(2+) by ethanol, chloral hydrate, or raised osmotic pressure.4. It is suggested that the specific action of K(+) is to increase the lability of nerve terminal Ca permeability with respect to depolarization of the nerve terminal membrane, while the slow effect of K(+) simply reflects nerve terminal depolarization, slow to become maximal because of diffusion barriers limiting access of raised K(+) to the Ranvier nodes of motor axons.

Animals↗