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Department of Medicine, Pulmonary Division, Case Western Reserve University and Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Van Lunteren, Erik, and Michelle Moyer. Effects of DAP
on diaphragm force and fatigue, including fatigue due to
neurotransmission failure. J. Appl.
Physiol. 81(5): 2214-2220, 1996.
Among the
aminopyridines, 3,4-diaminopyridine (DAP) is a more effective
K+ channel blocker than is
4-aminopyridine (4-AP), and, furthermore, DAP enhances neuromuscular
transmission. Because 4-AP improves muscle contractility, we
hypothesized that DAP would also increase force and, in addition,
ameliorate fatigue and improve the neurotransmission failure component
of fatigue. Rat diaphragm strips were studied in vitro (37°C). In
field-stimulated muscle, 0.3 mM DAP significantly increased diaphragm
twitch force, prolonged contraction time, and shifted the
force-frequency relationship to the left without altering peak tetanic
force, resulting in increased force at stimulation frequencies 
50 Hz.
During 20-Hz intermittent stimulation, DAP increased diaphragm peak
force compared with control during a 150-s fatigue run and,
furthermore, significantly improved maintenance of intratrain force.
The relative contribution of neurotransmission failure to fatigue was
estimated by comparing the force generated by phrenic nerve-stimulated
muscles with that generated by curare-treated field-stimulated muscles.
DAP significantly increased force in nerve-stimulated muscles and, in
addition, reduced the neurotransmission failure contribution to
diaphragm fatigue. Thus DAP increases muscle force at
low-to-intermediate stimulation frequencies, improves overall force and
intratrain fatigue during 20-Hz intermittent stimulation, and reduces
neurotransmission failure.
potassium channel; skeletal muscle; contractility; respiratory
muscle; 3,4-diaminopyridine
INTRODUCTION THE POTASSIUM CHANNEL-BLOCKING aminopyridines prolong
action potential duration, thereby increasing muscle contraction force (7, 28). Recent studies have found that 4-aminopyridine (4-AP) augments
force of diaphragm muscle strips at low-to-intermediate stimulation
frequencies (16, 30-32) and has variable effects on muscle fatigue
(30).
Although 4-AP has been used therapeutically in humans (25), it is
relatively toxic. 3,4-Diaminopyridine (DAP) is less convulsant (8, 9,
10, 33) and has been used for experimental medical treatments without
severe complicating side effects. For example, Bever and co-workers (4)
used DAP to improve the neurological deficits in patients with multiple
sclerosis, and McEvoy and co-workers (21) found that DAP is effective
in treating the motor and autonomic deficits of Lambert-Eaton
myasthenic syndrome, increasing muscle force by up to 81%.
Additionally, DAP has been shown to have greater K+ channel-blocking potency than
4-AP (14, 24). This would make DAP a potentially better agent than 4-AP
for muscle weakness and fatigue in a strategy directed toward
K+ channel blockade.
Previous investigators have shown that neurotransmission failure (NF)
is an important contribution to the development of fatigue (1, 15).
These authors propose that NF is due to axonal block of action
potential propagation, decreased transmitter release, decreased
end-plate excitability, or a combination of those events. Solving the
deficiencies at the neuromuscular junction by increasing the
neurotransmitter release could potentially reduce the NF contribution to fatigue. DAP increases transmitter release in the nervous system (5,
8-10, 20, 29), which is proposed to be secondary to an increase in
the calcium entry into the nerve terminal during an action potential
(28).
The purposes of the present study were to evaluate the effectiveness of
DAP in augmenting force during electrical stimulation, to observe the
effect of DAP on fatigue development, and to determine whether DAP
alters the relative contribution of neuromuscular transmission failure
to fatigue.
METHODS Studies were performed in vitro on diaphragm muscle of 250- to 350-g
Sprague-Dawely rats. The animals were anesthetized with urethan (1 g/kg), and the diaphragm was removed surgically. For several studies
the phrenic nerves were also dissected out and removed intact with the
diaphragm. The muscles were placed in oxygenated (95%
O2-5%
CO2) physiological solution
consisting of (in mM) 135 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 1 NaH2PO4,
15 NaHCO3, and 11 glucose, with
the pH adjusted to 7.3-7.4. Small strips (1-1.5 mm diameter)
were made, with care taken to keep the rib origin and central tendinous
insertion intact. For those studies in which the phrenic nerve was also
removed, identically sliced strips were made, each containing the nerve
connected to the diaphragm. The muscles were mounted vertically in a
double-jacketed bath (37°C) containing physiological solution.
Except as noted below, the muscles were field stimulated electrically
(1-ms pulse width, supramaximal voltage) at optimal length via platinum
electrodes, and force was measured with a high-sensitivity isometric
transducer (Kent Scientific/Radnotti Glass Technology, Monrovia, CA).
This method routinely produces diaphragm twitch tensions of ~0.5
kg/cm2 (30). With this stimulation
paradigm, addition of curare to the bath does not reduce muscle force,
indicating that the muscles are activated directly as opposed to via
phrenic nerve branches. A small group of muscle strips underwent
stimulation via the phrenic nerve by means of a suction electrode (A-M
Systems, Everett, WA) with a pulse width of 0.2 ms and supramaximal
voltage.
Diaphragm muscle strips underwent isometric twitch stimulation at a
frequency of 0.1 Hz to establish a baseline for twitch force. Muscle
strips in which force varied by >5% during the predrug baseline
period were rejected from further analysis. After the 3-min baseline
period, aliquots of DAP dissolved in physiological solution were added
to the bath, and twitch stimulation at 0.1 Hz was continued for 10 min
so that the muscle twitch force had stabilized after drug addition.
Additional physiological solution was added to control (no drug)
strips. For the muscle field-stimulated arm of the nerve vs. the muscle
field-stimulated study, d-tubocurare (12 µM) was added to the bath solution before stimulation to ensure that direct stimulation of intramuscular nerve branches was entirely absent. With the exception of muscle strips used to assess
dose-response and force-frequency relationships, all muscles then
underwent stimulation with 20-Hz trains. The train duration was 330 ms, and trains occurred every second. A stimulation frequency of 20 Hz was
chosen, because diaphragm motor units normally fire at a frequency of
10-30 Hz during breathing (26). In all protocols, n Muscle force records were digitized, collected on-line (Axotape, Axon
Instruments, Foster City, CA), and stored on the hard drive of a
computer. On-screen measurements of force were made with manually
controlled cursors. Isometric tension was measured in grams. Because of
interstrip variability in size, force was normalized relative to the
last three twitches during the baseline period. Isometric twitch
kinetics were quantified by measurements of the time to peak force
(contraction time) and the time for peak force to decay by 50%
(half-relaxation time) with use of single twitches or the first and
last twitch, respectively, of the tetanus. During fatigue, the plateau
phase of a tetanic contraction, normally maintained at a constant
force, decreases over time during each 20-Hz train (2, 27). To measure
this degree of intratetanic fatigue, the force at the end of the
330-ms-long train was measured and expressed as a percentage of the
maximum tetanic force within the same tetanus (force-330) (27).
The NF contribution to diaphragm fatigue was calculated by comparing
force loss during repetitive nerve stimulation with that during
repetitive muscle field stimulation with use of
procedure 2 of Kuei et al. (15). The
force decline during muscle field stimulation was due to muscle failure
(MF), whereas the force decline in nerve-stimulated muscles (F) was due
to the combined contribution of MF and NF. The formula was developed by
Aldrich et al. (1) and used by Kuei et al.: NF = (F Statistical analysis of the dose-response effects of DAP on prefatigue
force and isometric twitch kinetics was performed with one-way analysis
of variance followed by Dunnett's test. Statistical assessment of the
effects of DAP on the force-frequency relationship and on force and
twitch kinetics during fatigue runs was performed with two-way
repeated-measures analysis of variance followed by the Newman-Keuls
test. P < 0.05 (2-tailed) was
considered to indicate statistical significance.
RESULTS
Table 1.
Effects of 0.1-10 mM DAP on diaphragm isometric twitch force and
twitch kinetics
5. Reagents and drugs were
obtained from Sigma Chemical (St. Louis, MO).
MF)/(1 MF), where F and MF were calculated by the percentage of force
loss at each time point during nerve and muscle field stimulation, respectively.
Fig. 1.
Effects of 0.3 mM 3,4-diaminopyridine on diaphragm force during 0.1- and 20-Hz stimulation. Twitches are shown immediately before addition
of drug and after 10 min of 0.1-Hz stimulation with drug added; 20-Hz
trains are depicted at onset and after 20 and 60 s of intermittent
stimulation.
[View Larger Version of this Image (26K GIF file)]
No Drug
DAP, mM
0.1
0.3
1.0
3.0
10.0
Force
1.11 ± 0.05
1.80 ± 0.26
2.58 ± 0.17*
2.56 ± 0.13*
2.66 ± 0.51*
1.97 ± 0.22
Contraction time, ms
22.5 ± 1.0
24.5 ± 1.7
29.0 ± 0.6*
31.0 ± 1.7*
28.0 ± 0.8*
29.5 ± 0.5*
Half-relaxation
time, ms
21.0 ± 1.1
24.5 ± 2.5
23.0 ± 3.4
22.5 ± 2.6
20.0 ± 1.7
24.0 ± 1.5
Values are means ± SE. DAP, 3,4-diaminopyridine. Data for force
are maximum increases over 15 min after drug addition. Contraction time
and half-relaxation time are at time of maximum force increase.
*
Statistically significant differences between no drug and
different drug concentrations (P < 0.05).
50 Hz,
with the relative increase in force reaching a maximum of ~150% at a
stimulation frequency of 10 Hz.
) or with
0.3 mM 3,4-diaminopyridine (
). Curve is shifted to left because of
addition of 3,4-diaminopyridine. Force in all cases is normalized to
value for twitch force immediately before addition of drug or no drug.
Values are means ± SE. * Statistically significant differences between drug and no drug
(P < 0.05).
During long-term 20-Hz intermittent stimulation, in the absence of DAP, force progressively declined after an initial modest increase, whereas with DAP there was a larger initial potentiation of force before a decline in force (Fig. 3A). The effects of the DAP-induced force increase outweighed the subsequently more rapid rate of force decline over time, so that DAP increased diaphragm force for the fatigue run as a whole (P < 0.0001). Force-330, an evaluation of the ability of the muscle to maintain force during the plateau phase within the same tetanic stimulation, was improved by DAP during 20-Hz stimulation (P = 0.0016; Fig. 3B). Peak force was elevated significantly by DAP for the first half of the fatigue run (Fig. 3A), whereas force-330 was elevated significantly by DAP during the second half of the fatigue run (Fig. 3B).
, No drug; 
, 3,4-diaminopyridine. Values are
means ± SE. * Statistically significant differences between
drug and no drug (P < 0.05).
During repetitive 20-Hz stimulation the contraction time was significantly greater with than without DAP throughout the entire time frame (P = 0.0003; Fig. 4A); the extent of contraction time prolongation by DAP increased modestly over time. The half-relaxation time was also prolonged significantly by DAP (P < 0.0001; Fig. 4B), an effect that became considerably more pronounced over time. The substantially augmented prolongation of relaxation time by DAP during fatigue and the consequential enhanced temporal summation of force (Fig. 1) likely contributed to the better maintenance of peak force in DAP-treated muscle strips during the course of the fatigue run.
, No drug;
, 3,4-diaminopyridine. Values are means ± SE.
* Statistically significant differences between drug and no drug
(P < 0.05).
Phrenic nerve-stimulated muscle. DAP significantly increased force in nerve-stimulated muscle strips during 20-Hz stimulation (P = 0.007; Fig. 5A) and in a manner that was qualitatively similar to that seen with field-stimulated muscle (cf. Figs. 3A and 5A). Rate of force decline and effects of DAP on field-stimulated muscle strips were similar in curarized and noncurarized preparations (data not shown). During 20-Hz intermittent stimulation the NF contribution to diaphragm fatigue rose to 45% in the absence of DAP (Fig. 5B). With the addition of DAP, NF was considerably less, reaching a plateau of ~20%.
, No drug; , 3,4-diaminopyridine.
DISCUSSION
The results of the present study indicate that DAP is a more effective skeletal muscle inotropic agent than 4-AP (30, 32), causing a greater increase in muscle force without accentuating fatigue during 20-Hz stimulation. Not previously described for the aminopyridines is the fact that they also reduce the degree of intratrain fatigue and attenuate the neuromuscular component of fatigue.
Previous investigators have demonstrated the greater
K+ channel-blocking potency of DAP
than 4-AP. For example, Kirsch and Narahashi (14) measured
K+ channel conductance in squid
giant axons and found that 1 mM 4-AP causes a 75%
K+ current block, whereas 0.025 mM
DAP produces the same amount of K+
current block. These authors suggested that this greater affinity may
be due to the greater hydrogen-bonding ability of DAP. Molgo et al.
(23) measured stimulus-evoked transmitter release recorded as end-plate
potentials in single fibers of isolated mouse phrenic nerve-hemidiaphragm preparations. They found that DAP was six to seven
times more potent than 4-AP in this respect. Our results are consistent
with these findings, in that DAP augmented force to a greater extent
than 4-AP during low-to-intermediate stimulation frequencies (Fig.
6A). DAP
increased force an average of 137% over control values at stimulation
frequencies ranging from 1 to 30 Hz, whereas previous experiments
showed that 4-AP only increased force an average of 59% over this same
stimulation frequency range (32). In preliminary studies we found that
an increase in 4-AP concentration up to 2 mM did not augment diaphragm
force any more than 0.3 mM 4-AP, suggesting that the greater increase
in force with DAP than with 4-AP is not due to a shifted dose-response relationship.
, data from present
study) with 4-aminopyridine (
, data from Refs. 30 and 32) on rat
diaphragm. A: effects on
force-frequency relationships. B:
effects on force during repetitive 20-Hz stimulation. Force is
expressed as a percent change from average force generated by no-drug
control muscles studied at the same time.
DAP shifted the normal force-frequency response curve to the left. DAP prolongs action potentials as a consequence of a decreased rate of repolarization (6), thereby also prolonging contraction time. At a low-to-intermediate stimulation frequency, e.g., 20 Hz, prolongation of contraction time results in a higher degree of twitch fusion, causing an increase in force output. However, fusion is complete at high stimulation frequencies, e.g., 120 Hz, so that no additional force can be generated solely by prolonging contraction time.
The effects of DAP on muscle fatigue during 20-Hz field stimulation were qualitatively similar to previously reported effects of 4-AP (30), in that both agents increased force at the onset of stimulation, augmented the degree of force potentiation during the early part of repetitive stimulation, and improved force over time for the entire period of repetitive stimulation. A quantitative comparison of the effects of these two agents is depicted in Fig. 6B, which indicates similar quantitative effects of the two agents on muscle fatigue. During the course of fatigue, there was an especially prominent prolongation of relaxation time in the DAP-treated muscles (Fig. 4B); this prolongation of relaxation time was similar to that observed previously for 4-AP-treated muscles (30) and results in considerable temporal summation of force (Fig. 1), leading to a better preservation of peak force.
Force-330 is an estimate of the muscle's ability to maintain force during a short tetanic contraction. This measure of intratrain fatigue is believed to reflect high-frequency fatigue, as opposed to serial measurements of peak force over time (intertrain fatigue), which is believed to reflect low-frequency fatigue (27). At 20-Hz stimulation, force-330 was better preserved over time in the presence than in the absence of DAP, suggesting that it is possible to partially ameliorate high-frequncy fatigue with the aminopyridines. Renaud and Comtois (27) recently found that elevating extracellular K+ concentration further inhibited the maintenance of force during the plateau phase of a tetanic contraction in previously fatigued muscle, which is consistent with the present findings that preventing K+ efflux can reduce intratrain fatigue.
Two major categories of peripheral fatigue are contractile failure and transmission failure (3). Aldrich et al. (1) demonstrated a significant contribution of NF to muscle fatigue after high-frequency stimulation of isolated rat diaphragm, and Kuei et al. (15) noted that the relative contribution of NF to rat diaphragm fatigue increased progressively with higher rates of stimulation. Kuei et al. used two methods to estimate the neurotransmission component of fatigue: in procedure 1 they stimulated the phrenic nerve to produce fatigue and intermittently superimposed direct muscle stimulation, whereas in procedure 2 they compared separate groups of muscle strips that underwent fatiguing stimulation via field stimulation or via phrenic nerve stimulation (similar to the present study). A potential disadvantage of procedure 2 is that the field-stimulated muscle strips may maintain higher tensions than the nerve-stimulated muscles as fatigue develops and, hence, may be more susceptible to a contractile type of fatigue. This effect would reduce the differences between the tensions elicited by direct and indirect stimulation and could lead to an underestimate of transmission failure. However, Kuei et al. found slightly higher estimates for the maximal relative contribution of NF to fatigue during procedure 2 than during procedure 1, arguing that this issue is not a major concern. Furthermore, in the present study, the same technique was used for the DAP-treated and untreated muscles, so that any systematic effects of the technique on quantification of the neurotransmission component of fatigue should apply equally to DAP-treated and untreated muscles.
DAP has been found to enhance synaptic transmission at the neuromuscular junction (5, 9, 10, 12, 13, 17, 18, 22, 23, 28). With DAP we found that the NF contribution to neuromuscular fatigue was decreased at a stimulation frequency of 20 Hz. It is believed that DAP causes an increased amount of neurotransmitter release. Katz and Miledi (12) measured end-plate potentials in frog muscle fiber to show that the amount of quantal neurotransmitter packets released per nerve impulse was several thousand with the addition of DAP compared with an average of only 300 without the drug. Also, electron-microscopic studies of motor nerve terminals show a large increase in the number of synaptic vesicles at the release site in the frog neuromuscular junction when an aminopyridine is present compared with no aminopyridine (11). The mechanisms of increased neurotransmitter release are still under debate; however, several common possibilities have been proposed on the basis of the belief that the neurotransmitter increase is due to an increased calcium flux at presynaptic nerve terminals (20). This may occur by the blockade of K+ channels (22), by an increase in the voltage-dependent calcium conductance in the nerve terminals (19), or by prolongation of the action potential at the nerve terminal (18, 22). The failure of the aminopyridines to enhance neurotransmitter release without calcium indicates that calcium flux at presynaptic terminals does play a key role in the increased amount of neurotransmitter released when DAP is present (18, 22).
The present study was performed in vitro, so effects of DAP may differ in vivo from those found here. For example, in vivo muscle fibers contract asynchronously in response to phrenic nerve traffic, whereas in vitro they contract synchronously in response to electrical stimulation. Furthermore, in vivo blood flow is intact and can be modulated in response to the metabolic demands of the muscle. These factors may have important influences on the muscle, especially during fatigue. On the other hand, the in vitro preparation has been used extensively for studies of muscle contractility and fatigue (1, 2, 6, 15, 16, 30-32) and has the advantage of isolating the muscle tissue from potentially confounding systemic influences. Thus it is possible that in vivo DAP may influence the pattern of phrenic motoneuronal recruitment and/or diaphragm blood flow and, hence, affect diaphragm performance indirectly. The present study was designed to assess the direct effects of DAP on the muscle and the neuromuscular junction, which was the rationale for the in vitro approach.
In conclusion, the present data indicate that DAP improves diaphragm contractile performance to an extent that is at least as great as that previously reported for 4-AP (16, 30, 32). In addition, we found that DAP improves intratrain fatigue and reduces the NF contribution to fatigue. Inasmuch as DAP has been associated with fewer adverse effects than 4-AP when administered to humans, DAP appears to be a better agent than 4-AP for future in vitro studies of the effects of the aminopyridines on muscle contractile performance.
ACKNOWLEDGEMENTS
This study was supported in part by the Veterans Affairs Medical Research Service and by National Heart, Lung, and Blood Institute Grant HL-42215.
FOOTNOTES
Address for reprint requests: E. van Lunteren, Pulmonary Section 111J(W), Cleveland VA Medical Center, 10701 East Blvd., Cleveland, OH 44106-1782.
Received 26 December 1995; accepted in final form 29 May 1996.
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 E. van LUNTEREN and M. MOYER Electrophysiologic and Inotropic Effects of K+-Channel Blockade in Aged Diaphragm Am. J. Respir. Crit. Care Med., September 1, 1998; 158(3): 820 - 826. [Abstract] [Full Text] [PDF]
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E. Van Lunteren, M. Moyer, and A. Torres ATP-sensitive K+ channel blocker glibenclamide and diaphragm fatigue during normoxia and hypoxia J Appl Physiol, August 1, 1998; 85(2): 601 - 608. [Abstract] [Full Text] [PDF]
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