Vol. 86, Issue 3, 1009-1016, March 1999
Peptide toxin blockers of voltage-sensitive
K+ channels: inotropic effects on
diaphragm
Erik
van Lunteren and
Michelle
Moyer
Departments of Medicine and Neurosciences, Cleveland Veterans
Affairs Medical Center and Case Western Reserve University,
Cleveland, Ohio 44106
 |
ABSTRACT |
Agents that block many types of
K+ channels (e.g., the
aminopyridines) have substantial inotropic effects in skeletal
muscle. Specific blockers of ATP-sensitive and
Ca2+-activated
K+ channels, on the other hand, do
not, or minimally, alter the force of nonfatigued muscle, consistent
with a predominant role for voltage-gated
K+ channels in regulating muscle
force. To test this more directly, we examined the effects of peptide
toxins, which in other tissues specifically block voltage-gated
K+ channels, on rat diaphragm in
vitro. Twitch force was increased in response to 
-, 
-, and
-dendrotoxin and tityustoxin K (17 ± 6, 22 ± 5, 42 ± 14, and 13 ± 5%; P < 0.05, < 0.01, < 0.05, < 0.05, respectively) but not in response to
-dendrotoxin or BSA (in which toxins were dissolved). Force during
20-Hz stimulation was also increased significantly by -, -, and
-dendrotoxin and tityustoxin K. Among agents, increases in twitch
force correlated with the degree to which contraction time was
prolonged (r = 0.88, P < 0.02). To determine whether
inotropic effects could be maintained during repeated contractions,
muscle strips underwent intermittent 20-Hz train stimulation for a
duration of 2 min in presence or absence of -dendrotoxin. Force was
significantly greater with than without -dendrotoxin during
repetitive stimulation for the first 60 s of repetitive contractions.
Despite the ~55% higher value for initial force in the presence vs.
absence of -dendrotoxin, the rate at which fatigue occurred was not
accelerated by the toxin, as assessed by the amount of time over which
force declined by 25 and 50%. These data suggest that blocking
voltage-activated K+ channels may
be a useful therapeutic strategy for augmenting diaphragm force,
provided less toxic blockers of these channels can be found.
skeletal muscle; contraction; fatigue; dendrotoxin; tityustoxin
| |
INTRODUCTION |
THE AMINOPYRIDINES and tetraethylammonium, which block
many types of K+ channels, prolong
action potential duration and thereby increase twitch force of skeletal
muscle (8, 16, 17, 19, 31-33). The magnitude of
twitch-force augmentation (increase of 30-75% for
tetraethylammonium and 4-aminopyridine, and 60-160% for
3,4-diaminopyridine) and the persistence of the force increase over
time during repetitive stimulation (in particular for
3,4-diaminopyridine) are such that K+-channel blockers are a
potentially useful group of skeletal muscle inotropic agents. Specific
blockers of ATP-sensitive and
Ca2+-activated
K+ channels, on the other hand, do
not or only minimally alter force of nonfatigued muscle (18, 34, 36).
This is consistent with a predominant role for voltage-gated
K+ channels in regulating muscle
force. However, this role has been difficult to test directly because
of the paucity of agents that specifically block the latter channels.
Recently a number of peptide toxins were identified that specifically
block voltage-gated K+ channels in
neurons, Schwann cells, and smooth muscle cells (2-4, 11, 21, 24,
25). These include -, -, -, and -dendrotoxin isolated from
the venom of the Eastern green mamba snake Dendroaspis angusticeps and tityustoxin K isolated from the
Brazilian scorpion Tityus serrulatus.
The - and -dendrotoxin appear to block rapidly inactivating
voltage-gated ("A-type") K+
channels preferentially, whereas the other three toxins preferentially block noninactivating voltage-gated (delayed-rectifier)
K+ channels (3, 25). The actions
of these peptide toxins on skeletal muscle contractility have not been
examined. We hypothesized that these agents would increase skeletal
muscle force and that the induced force increases would be maintained
over time during repetitive contractions.
| |
METHODS |
Studies were performed in vitro on diaphragm muscle of 250- to 300-g
male Sprague-Dawley rats. The animals were anesthetized with urethan
(1-1.5 g/kg), and the diaphragm was removed surgically. The
muscles were placed in physiological solution comprised as follows (in
mM): 135 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 1 NaHPO4, 15 NaHCO3, and 11 glucose, with pH
adjusted to 7.35-7.45 while being aerated with 95%
O2-5%
CO2. Small strips (1-1.5 mm
diameter) were made with the rib origin and central tendinous insertion kept intact. The muscle strips were mounted vertically in an oxygenated double-jacketed bath (temperature 37°C) and underwent field
electrical stimulation (pulse width 1 ms, supramaximal voltage) at
optimal length via platinum electrodes. With this technique, we have
verified that muscles are being activated directly rather than
indirectly via nerve branches, based on
d-tubocurare not diminishing the magnitude of twitch force (29, 30, 32) and not altering force and
fatigue during repetitive 20-Hz stimulation (based on data from Ref.
31). Isometric tension was measured in grams with a high-sensitivity
isometric transducer (Kent Scientific/Radnoti Glass Technology,
Monrovia, CA).
Diaphragm muscle strips underwent isometric twitch stimulation at a
frequency of 0.1 Hz for a baseline period of 3 min. Muscle strips in
which force varied by >5% during the 3-min period were rejected from
further analysis, because baseline instability would prevent accurate
quantification of toxin effects. After the baseline period, aliquots of
peptide toxins dissolved in physiological solution plus 0.1% BSA were
added to the bath, and twitch stimulation at 0.1 Hz was continued.
Control strips had additional physiological solution plus 0.1% BSA
added to the bath at this time. Sample sizes for all studies were five
or more muscle strips. Studies used a single concentration
of each toxin (-dendrotoxin, 500 nM; tityustoxin K, 50 nM; and
-, -, and -dendrotoxin, 100 nM), which was chosen based on the
degree of K+ current or efflux
inhibition in other studies (2, 3, 11, 21, 24, 25). A single, moderate
concentration of each toxin was used, because at high concentrations
the dendrotoxins lose their selectivity against inactivating vs.
noninactivating voltage-gated K+
channels (3). Peptide toxins were obtained from Alomone Labs (Jerusalem, Israel), and other reagents were obtained from Sigma Chemical (St. Louis, MO). To assess the effects of
K+-channel blockade on changes in
force over time during repetitive stimulation, muscle strips underwent
a 20-Hz fatigue protocol (train duration 0.33 s, with 1 train delivered
per second) for 2 min. These studies focused on a single agent, picked
on the basis of the greatest increase in force during twitch and 20-Hz stimulation. The muscle strips were incubated with either
-dendrotoxin (100 nM) dissolved in 0.1% BSA or an equal volume of
0.1% BSA alone for 5 min before the onset of the fatigue protocol.
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 to report peak forces. To account for 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).
Effects of -dendrotoxin on fatigue at 20 Hz were evaluated by
comparing changes in normalized peak force over time, as well as the
time required for peak force to decrease by 25 and 50% of initial
values. Intratrain fatigue was assessed during 20-Hz stimulation by
measuring the force at the end of the 330-ms-long train and expressing
this as a percentage of the maximum force within the same tetanus
(force-330) (Ref. 33, and as modified from Ref. 18). Isometric twitch
kinetics were also measured during fatigue and were estimated from the first and last twitch of each train. Statistical analysis of the effects of toxins on twitch force, 20-Hz force, contraction time, and
half relaxation time was performed with the paired
t-test. Statistical analysis for data
on force over time during repetitive contractions was done with two-way
ANOVA for repeated measures followed by the Newman-Keuls test when the
ANOVA indicated statistical significance. A
P value of <0.05 (2 tailed)
indicated significance.
| |
RESULTS |
Effects of peptide toxins on force and isometric contractile
kinetics.
BSA, in which the peptide toxins were dissolved, had no effects on
muscle force (Table 1). An example of the
effects of -dendrotoxin on muscle twitch force is depicted in Fig.
1A.
Increases in twitch force and force during 20-Hz stimulation were noted
with -dendrotoxin, -dendrotoxin, -dendrotoxin, and tityustoxin
K but not with -dendrotoxin (Table 1). The magnitude of the
twitch-force increase was especially prominent for -dendrotoxin
(42%). For the group of agents, the magnitude of the increase in
twitch force correlated significantly with the increase in 20-Hz force
(Fig. 2,
left). Isometric contraction time
was prolonged significantly by -, -, and -dendrotoxin, and
isometric half relaxation time was prolonged significantly by - and
-dendrotoxin (Fig. 1B for
-dendrotoxin and Table 1 for all toxins). The increases in twitch
force correlated significantly with the prolongations of contraction
time (Fig. 2, right), and there was
a trend for the increases in 20-Hz force to correlate with the
prolongations of contraction time (r = 0.77, P = 0.07, data not shown).
However, increases in twitch or 20-Hz force did not correlate with the
degree to which the half relaxation time was prolonged (data not
shown).
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Table 1.
Effects of BSA, dendrotoxins, and tityustoxin on diaphragm force during
isometric twitch and 20-Hz contractions and on isometric twitch
contraction time and half relaxation time
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Fig. 1.
A: example of change in diaphragm
muscle twitch force in response to -dendrotoxin (100 nM). Twitches
depicted are during baseline period
(left), as well as 1, 3, and 5 min
after drug addition (right).
B: time-expanded record of diaphragm
twitch force in response to -dendrotoxin (5 min after drug addition)
is superimposed on force during baseline (control) period.
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Fig. 2.
Relationship for all five peptide toxins and BSA (vehicle) between
increase in twitch force and prolongation of contraction time
(left), and between increase in
twitch force and increase in force during 20-Hz stimulation
(right). Linear correlations are
indicated.
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Effects of -dendrotoxin on force during repetitive
stimulation.
To determine whether force increases could be maintained over time,
muscle strips underwent repetitive 20-Hz train stimulation for a
duration of 2 min in the presence or absence of -dendrotoxin. An
example of force recordings is depicted in Fig.
3. Force was significantly greater with
than without -dendrotoxin during repetitive stimulation for the
first 60 s of repetitive contractions (Fig. 4,
left). Despite the ~55% higher
value for initial force in the presence than in the absence of
-dendrotoxin, the rate at which fatigue occurred was not accelerated
by the toxin, as assessed by the amount of time over which force
declined by 25 and 50% (Fig. 4,
right). Intratrain fatigue, assessed
by force-330, was also not affected by -dendrotoxin (Fig.
5). Contraction time remained
relatively stable over the course of repetitive stimulation, whereas
half relaxation time was gradually prolonged during the first one-half
of the stimulation period before reaching a plateau. -Dendrotoxin
had no significant effects on the changes in contraction or
half relaxation time during repetitive contractions (Fig.
6).
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Fig. 3.
Example of diaphragm muscle force during repetitive 20-Hz stimulation
in presence of -dendrotoxin (100 nM). Shown are (from
left to
right) predrug twitch force, predrug
force during 20-Hz train, postdrug twitch force, and postdrug force at
onset as well as after 1 and 2 min of repetitive 20-Hz train
stimulation.
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Fig. 4.
Effects of -dendrotoxin (100 nM) on force over time during
repetitive contractions elicited by 20-Hz train stimulation.
Left: values for force over time in
presence and absence of the toxin. * Significant differences
between muscle strips treated with toxin dissolved in BSA and those
treated with BSA alone, P < 0.05. Right: time over which force declined
by 25 and 50% during repetitive stimulation for
-dendrotoxin-treated and untreated muscle strips. Values are means ± SE.
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Fig. 5.
Effects of -dendrotoxin on intratrain fatigue, as quantified by the
force-330, which is quantified by measuring force at end of the
330-ms-long train and expressing this as %maximum force within the
same tetanus. There were no significant differences between muscles
treated with -dendrotoxin and those treated with BSA alone. Values
are means ± SE.
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Fig. 6.
Changes in isometric contraction and half relaxation times during
course of repetitive 20-Hz stimulation in muscle strips treated with
toxin dissolved in BSA and those treated with BSA alone. Values are
means ± SE.
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DISCUSSION |
Methodological issues.
The present study examined only a single concentration of each toxin,
rather than evaluating full-dose-response relationships. This approach
was based on several considerations. First and foremost was the desire
to use concentrations at which specificity may be preserved. The major
issue with previous studies of the aminopyridines and
tetraethylammonium (which block multiple types of
K+ channels) has been whether
these agents indeed exert their inotropic effects by blocking
voltage-sensitive K+ channels
rather than other types of K+
channels. In the present study, using agents at concentrations that in
other tissues specifically block voltage-sensitive
K+ channels provides considerable
mechanistic insight into the role of voltage-sensitive
K+ channels in muscle
contractility. In contrast, using higher concentrations of these agents
would not provide any more mechanistic insight than what has been
gained previously from the aminopyridines and tetraethylammonium.
Second, these agents are highly toxic, with the dendrotoxins, for
example, being derived from one of the most poisonous snakes in the
world (green mamba snake). Therefore, testing higher doses to see if
they may be associated with greater therapeutic effect would not be
very useful, as toxicity would prohibit their use in vivo. As a result,
the present study is of more mechanistic than therapeutic importance,
and, hence, knowing the magnitude of the force increases that can be
achieved with higher (but less specific) doses will not be very useful.
Third, these agents are in limited supply and extremely expensive, so that examining effects of concentrations 100-fold or more higher than
those used is not justified, given the limited useful information that
would be obtained from performing full-dose-response evaluations.
Effects of peptide toxins that block voltage-sensitive
K+ channels.
The major finding of the present study was that several peptide toxin
blockers of voltage-gated K+
channels increased diaphragm force during twitch and subtetanic stimulation and that the force increase in response to -dendrotoxin could be maintained over the course of 60 s during repetitive contractions. These actions are similar in some but not all respects to
those previously described for the aminopyridines (8, 16, 17, 19,
31-33), which block delayed-rectifier as well as other K+ channels (2, 6, 9, 10, 22).
Benishin et al. (3) identified four polypeptide components of Eastern
green mamba snake venom. -Dendrotoxin corresponded to the previously
described "dendrotoxin" (12) and toxin
C13S2C3 (15), -dendrotoxin corresponded to the previously described toxin
C13S1C3
(15), and - and -dendrotoxin have not been described previously.
The COOH-terminal segments of all four toxins are homologous. The
NH2-terminal portions of - and
-dendrotoxin have some sequence homologies, but they have no
homologies with - and -dendrotoxin (3). The - and
-dendrotoxin preferentially block inactivating voltage-gated
K+ channels, whereas - and
-dendrotoxin preferentially block noninactivating voltage-gated
K+ channels; however, the
preferential activity diminishes at high concentrations (3). Nearly all
available data indicate that the dendrotoxin family is specific for one
or more different types of voltage-sensitive
K+ channels (28). Two toxins
isolated from the Brazilian scorpion Tityus
serrulatus, tityustoxin K and K, have similar
actions in blocking noninactivating voltage-gated
K+ channels (4, 25). Tityustoxin
K has partial sequence homology at the COOH-terminal (but not the
NH2-terminal) segment with
charybdotoxin and noxiustoxin (scorpion toxins that block
large-conductance Ca2+-activated
K+ channels), whereas the larger
tityustoxin K is nonhomologous (25). The tityustoxins are also
nonhomologous with respect to the dendrotoxins. Both tityustoxins
appear to be specific for voltage-gated
K+ channels (4, 25), although
fewer data are available on this issue for the scorpion toxins than for
the dendrotoxins.
-Dendrotoxin (named dendrotoxin in older studies) augments
acetylcholine release from the neuromuscular junction (1, 12). Harvey
and Karlsson (12) found that this toxin augmented twitch force of
indirectly stimulated (nerve-stimulated) chick biventer cervicis muscle
by 200-250% but did not augment muscle force during direct
(field) stimulation or in response to KCl. Subsequently, Anderson and
Harvey (1) confirmed a presynaptic site of action in frog and rodent
muscle by demonstrating augmented excitatory end plate potentials due
to increased quantal content. In contrast to Harvey and Karlsson (12),
we found that -dendrotoxin produced a small increase in twitch force
(17%) in directly stimulated muscle. A possible explanation for the
discrepancy between the present study and that of Harvey and Karlsson
(12) is that mammalian muscle differs from avian muscle in
K+-channel structure. This was
also proposed by Harvey and Marshall (13) when they found that the
K+-channel blocking aminopryidines
augmented both directly and indirectly elicited twitches in rat
hemidiaphragm but augmented only indirectly elicited twitches in chick
biventer cervicis muscle.
The toxins used in the present study differ in the relative extent to
which they block noninactivating (presumably delayed-rectifier) vs.
inactivating (presumably A-type) voltage-gated
K+ channels, based on studies in
tissues other than skeletal muscle. As a result, one would predict
greater force increases in response to the toxins that are especially
effective at blocking the former channels (- and -dendrotoxin and
tityustoxin K) than in response to the toxins that are especially
effective at blocking the latter channels (- and -dendrotoxin).
The present study was not specifically designed to address this issue,
having used only a single concentration of each toxin, which,
furthermore, varied among toxins. The rationale for this approach is
that at high concentrations the dendrotoxins lose their selectivity
against inactivating vs. noninactivating voltage-gated
K+ channels (3). Nonetheless, some
suggestive trends can be noted among the dendrotoxins, in that three of
them were used in the same concentration and the fourth was used in a
higher concentration but had a relatively small effect. The magnitude
of the increases in twitch force was consistent with the prediction
based on blockers of noninactivating
K+ channels having greater
inotropic effects than blockers of inactivating K+ channels. Formal dose-response
studies would be needed to better address differences in inotropic
activity among peptide toxins, although because of loss of selectivity
at high doses, these studies would not definitively address the
relative importance of the above two types of voltage-gated
K+ channels.
The magnitude of the increase in twitch force for -dendrotoxin is at
the low end of the range previously described in rodent diaphragm
muscle for 4-aminopyridine (35-65% increase) and especially 3,4-diaminopyridine (60-160% increase) (8, 19, 31-33).
Several possible explanations need to be considered. The first is that -dendrotoxin was used in only a single concentration, whereas the
above-described increases in force in response to the aminopyridines are at doses associated with maximal or near-maximal effects. It is,
therefore, very likely that higher concentrations of peptide toxins may
have greater effects than that reported here. Second, the peptide
toxins block only voltage-gated K+
channels, whereas the aminopyridines block non-voltage-gated as well as
voltage-gated K+ channels. It is
possible that the actions of the aminopyridines on the former may have
contributed to their inotropic effects. This seems less likely, in that
specific blockers of other types of
K+ channels (e.g., glibenclamide,
apamin, charybdotoxin) have no or minimal inotropic effects in
nonfatigued skeletal muscle (18, 34, 36). Third, multiple
delayed-rectifier channels can be found in a single cell, including
skeletal myocytes (20), and it is possible that the aminopyridines are
more effective in blocking one or more of them than are the
dendrotoxins and tityustoxins. The latter notion is supported by data
from rabbit Schwann cells, in which type I and II delayed-rectifier
currents are both blocked by micromolar concentrations of
4-aminopyridine, but only type I current is blocked by nanomolar
concentrations of -dendrotoxin (2).
The peptide toxins prolonged contraction time and/or half
relaxation time to various extents. For the group, increases in twitch
force correlated with the degree to which the rate of contraction was
slowed but not with the degree to which the rate of relaxation was
slowed. The magnitude of twitch-force increases was approximately double that of the magnitude of contraction-time prolongation. This
indicates that the force increases were due to both a faster rate and a
longer period of tension development, similar to that seen with the
aminopyridines (8, 16, 19, 31-33).
Effects of K+-channel blockers on
muscle force during repetitive contractions depend not only on the
magnitude of the positive inotropism but also on the influences of
these agents on fatigue. These latter effects have not been delineated
fully. On the one hand, efflux of
K+ and influx of
Na+ occur during repetitive
contractions, which may depolarize the cell membrane and reduce
membranous excitability. This is postulated to contribute to fatigue,
particularly during high-intensity contractions (7, 26, 35). Reduction
of K+ conductance can, therefore,
potentially attenuate the extent to which, and the rate at which,
fatigue develops. On the other hand, as a result of their positive
inotropic effects, K+-channel
blockers can potentially accelerate other processes that lead to
fatigue (e.g., depletion of energetic substrates, accumulation of
lactate with reduction in intracellular pH). The effects of K+-channel blockade on force
during repetitive contractions have been examined previously for
specific blockers of ATP-sensitive K+ channels (e.g., glibenclamide;
Refs. 18, 34, 36) and for blockers of multiple types of
K+ channels (e.g., the
aminopyridines; Refs. 31, 32). The former agents have minimal to no
inotropic effects in nonfatigued muscle and in most studies have been
found not to alter the rate of force decline. The latter agents have
large inotropic effects in nonfatigued muscle stimulated at subtetanic
frequencies and accelerate the rate at which peak force declines over
time but attenuate intratrain fatigue. The net effects of these
processes in response to the aminopyridines appear to depend on
stimulation frequency. During 5-Hz stimulation, the accelerated rate of
fatigue outweighs the positive inotropic effect, so that with
4-aminopyridine force is higher initially but lower later during the
course of a fatiguing stimulus. On the other hand, during 20-Hz
stimulation, the positive inotropic effects of the aminopyridines
outweigh the accelerated rate of fatigue, so that force remains
augmented by these agents for the entire duration of stimulation.
The effects of -dendrotoxin on muscle force over time resemble those
reported previously for the aminopyridines (31, 32) in some but not all
respects. On the one hand, both agents increase force at the onset of
repetitive stimulation, and this force increase is maintained over
time, never decreasing to values below that of untreated muscle strips.
On the other hand, the aminopyridines accelerate intertrain fatigue but
alleviate intratrain fatigue, whereas -dendrotoxin affected neither
intertrain nor intratrain fatigue. The reasons for these differences
are not entirely clear, but several possibilities warrant
consideration. First is that the force increase at the onset of 20-Hz
stimulation was greater for the aminopyridines than for
-dendrotoxin. As a result, other cellular processes that lead to
fatigue may have been accelerated to a greater extent by the
aminopyridines than by -dendrotoxin, leading to greater intertrain
fatigue with the aminopyridines. Second, as discussed above,
aminopyridines appear to block voltage-gated K+ channels to a greater extent
than do the dendrotoxins. Consequentially, the
K+ efflux that is felt to
contribute most prominently to high-frequency fatigue (and therefore
contribute in particular to intratrain fatigue) may have been
attenuated more effectively by the aminopyridines than by
-dendrotoxin.
In conclusion, the present study indicates that specific blockers of
voltage-gated K+ channels augment
diaphragm force and that the inotropic effects can be maintained over
time during repetitive contractions. Future studies are needed to
examine the effects of these toxins on muscle action potentials, in
particular to verify that agents that have greater actions on
delayed-rectifier K+ channels
cause a greater degree of action potential prolongation than those with
greater actions on A-type K+ channels.
The agents used in the present study are all highly toxic, being
derived from snake and scorpion venoms, thus prohibiting their use in
vivo. Whether less toxic specific blockers of muscle voltage-gated
K+ channels can be developed is
unclear and depends on the degree to which these channels differ
structurally from voltage-gated K+
channels in other tissues. Muscle and nerve
Na+ channels are sufficiently
different from each other that it is possible to block the former
without blocking the later with µ-conotoxin from the marine snail
Conus geographicus (5, 14, 23, 27). The K+-channel family is
characterized by tremendous diversity, so it is possible that there is
sufficient diversity in their structure among tissues that selective
blockade of muscle voltage-gated K+ channels would be possible. Use
of high-selective blockers may allow muscle force to be increased
without producing central nervous system toxicity, which is, presently,
a limiting factor with the clinical use of the aminopyridines.
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ACKNOWLEDGEMENTS |
This study was supported by the Veterans Affairs Medical Research
Service and by National Institutes of Health Specialized Center of
Research Grant HL-42215.
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FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: E. van Lunteren, Pulmonary Section
111J(W), Cleveland VA Medical Center, 10701 East Blvd., Cleveland, OH
44106 (E-mail: exv4{at}po.cwru.edu).
Received 16 April 1998; accepted in final form 19 November 1998.
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