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ATP-sensitive Kϩ channel blocker glibenclamideand diaphragm fatigue during normoxia and hypoxia ERIK VAN LUNTEREN, MICHELLE MOYER, AND AUGUSTO TORRESDepartments of Medicine and Neurosciences, Case Western Reserve University,and Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106 Van Lunteren, Erik, Michelle Moyer, and Augusto
may potentially account for some of the discrepant Torres. ATP-sensitive Kϩ channel blocker glibenclamide and
diaphragm fatigue during normoxia and hypoxia. J. Appl. The purpose of the present study was to reexamine Physiol. 85(2): 601–608, 1998.—The role of ATP-sensitive Kϩ the issue of whether blocking KATP affects muscle channels in skeletal muscle contractile performance is contro- performance during repetitive contractions leading to versial: blockers of these channels have been found to not fatigue by 1) systematically addressing effects of stimu- alter, accelerate, or attenuate fatigue. The present study lation paradigm, temperature, and presence of hypoxia; reexamined whether glibenclamide affects contractile perfor- 2) comparing intertrain with intratrain fatigue; and 3) mance during repetitive contraction. Experiments systemati- assessing the rate of muscle relaxation, which is known cally assessed the effects of stimulation paradigm, tempera- to slow during fatigue (10, 11, 16, 19, 26). We found that ture, and presence of hypoxia and in addition comparedintertrain with intratrain fatigue. Adult rat diaphragm muscle the KATP blocker glibenclamide significantly improves strips were studied in vitro. At 37°C and normoxia, glibencla- intratrain but not intertrain fatigue but only under mide did not significantly affect any measure of fatigue hypoxic and not normoxic conditions and that it slows during continuous 5- or 100-Hz or intermittent 20-Hz stimu- rate of muscle relaxation during fatigue under both lation but progressively prolonged relaxation time during normoxic and hypoxic conditions but not at low tempera- 20-Hz stimulation. At 20°C and normoxia, neither force nor ture. These findings indicate that KATP may be acti- relaxation rate was affected significantly by glibenclamide vated during repetitive contraction, especially during during 20-Hz stimulation. At 37°C and hypoxia, glibencla- higher intensity contractions and/or under hypoxic mide did not significantly affect fatigue at 5-Hz or intertrain fatigue during 20-Hz stimulation but reduced intratrainfatigue and prolonged relaxation time during 20-Hz stimula- tion. These findings indicate that, although ATP-sensitive Kϩchannels may be activated during repetitive contraction, Male Sprague-Dawley rats (250–350 g) were anesthetized their activation has only a modest effect on the rate of fatigue with intraperitoneal urethan (1–1.5 g/kg), the diaphragmswere removed surgically, and two to four small strips (diam- eter ϳ1–1.5 mm) were cut per animal, with care taken to diaphragm; skeletal muscle; potassium; ATP-sensitive Kϩ preserve the attachment of the muscle to the central tendon and ribs. The muscle strips were mounted in physiologicalsolution at optimal length and were stimulated via platinumelectrodes by using a pulse width of 1 ms and supramaximalvoltages (Grass Instruments, West Warwick, RI). The aerated 2-5% CO2) physiological solution contained (in mM) density in many tissues, including skeletal muscle (7).
135 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 1 NaH2PO4, 15 In intact skeletal muscle fibers these channels are NaHCO3, and 11 glucose, with the pH adjusted to 7.35–7.45.
Bath temperature was controlled at 20 or 37°C by circulating generally closed under resting normoxic conditions (2, water of the appropriate temperature through the outer 3, 15). However, KATP open under conditions of low ATP jacket of the tissue baths (Radnoti Glass, Monrovia, CA).
concentration ([ATP]), low intracellular pH, and meta- Isometric tension was measured with a high-sensitivity trans- bolic poisoning (2, 7, 9, 22). It has been postulated that ducer (Kent Scientific/Radnoti Glass, Monrovia, CA). Twitch KATP become activated during repetitive muscle contrac- forces of ϳ0.5 kg/cm2 are obtained with this methodology in tion especially during high-intensity contractions and/or rat diaphragm (25). Force records were digitized, collected under hypoxic stress, which thereby contributes to Kϩ online with a computer (Axotape software, Axon Instruments, efflux and the development of skeletal muscle fatigue Foster City, CA), and stored for later data analysis. Drugs andreagents were obtained from Sigma Chemical (St. Louis, MO). Glibenclamide was dissolved as a 2 mM stock solution In support of the above postulate, studies utilizing in 0.05 M NaOH, the proper volume of which was added to the openers of KATP generally concur that these agents bath to produce a final concentration of 100 µM (16).
accelerate fatigue, especially under hypoxic conditions Diaphragm muscle strips were allowed to equilibrate and (12, 28, 30). In contrast, studies utilizing blockers of subsequently underwent twitch stimulation at 0.1 Hz for 3 min. Muscle strips were accepted for study only if twitch force have found variable effects on fatigue: many studies have found no significant effect on fatigue (5, varied by no more than 5% during the 3-min baseline period.
12, 16, 28, 30), although an improvement (13, 14, 30) Six separate experiments were performed, the conditions ofwhich are summarized in Table 1. Muscle strips were random- and a worsening (6) of fatigue have also been reported.
ized across arms of a given experiment but not across The methodology of these studies varies considerably experiments. That is, muscle strips were randomized to with respect to temperature, stimulation paradigm, receive drug or no drug under a given set of experimental presence of hypoxia, and data-analysis strategies, which conditions; assignment of muscle strips was not randomized 8750-7587/98 $5.00 Copyright ௠ 1998 the American Physiological Society Table 1. Stimulation frequencies, bath conditions, All values presented are means Ϯ SE. Statistical analysis of the effects of glibenclamide on prefatigue isometric twitch and sample sizes of the six experiments kinetics was performed with the unpaired t-test. Statistical analysis of the effects of glibenclamide on peak force, force-330, and half relaxation times during fatigue runs was performed with two-way ANOVA for repeated measures, followed in the event of a significant ANOVA by the Newman- Keuls test. The criterion for statistical significance was set at Normoxic conditions (37°C). Under normoxic condi- tions in nonfatigued muscle, glibenclamide (100 µM)did not significantly affect isometric twitch contractionor half relaxation times, although there was a nonsig- across all six experimental conditions. Care was taken to nificant trend for the latter to be prolonged (Table 2). In ensure that muscle strips from a given animal were assigned response to repetitive stimulation, glibenclamide did to both drug and no drug. Each muscle strip was used onlyonce. Experiments A–C and E–F were conducted at 37°C, not significantly affect peak force over time during 5-, whereas experiment D was conducted at 20°C. After the 20-, or 100-Hz stimulation under normoxic conditions baseline period, glibenclamide (100 µM) or vehicle (contain- at 37°C (Fig. 1). Force-330, an evaluation of the ability ing an equal volume of 0.05 M NaOH) was added to the bath of the muscle to maintain force during the plateau for all experiments, which was followed by an equilibration phase within the same tetanic stimulation (evaluated period of 4 min. For experiments E–F only, the gas with which during 20-Hz trains), was slightly but not significantly the solution was aerated was subsequently switched to 95% improved by glibenclamide under normoxic conditions N2-5% CO2 followed by an equilibration period of 4 min. Bath (Fig. 2). However, the extent to which the half relax- oxygen tension was measured in some of the hypoxia studies ation time progressively prolonged during repetitive with a dissolved-oxygen meter (ISO-2, World Precision Instru- stimulation was augmented significantly by glibencla- ments, Sarasota, FL) and averaged 3.8 Ϯ 0.8% at the end ofthe 4-min equilibration period. The muscles were stimulated mide during 20-Hz and to a lesser extent 5-Hz stimula- at 0.1 Hz to monitor twitch tension during all of the above.
Finally, the muscle strips underwent one of three stimulation Effects of lowering temperature (normoxia). Effects of paradigms: continuous 5-Hz stimulation (experiments A and lowering temperature to 20°C were assessed during E), intermittent 20-Hz stimulation (train duration 0.33 s, fatigue produced by 20-Hz stimulation. At this tempera- with 1 train delivered every second) (experiments B, D, and ture, glibenclamide had no significant effect on baseline F), or continuous 100-Hz stimulation (experiment C). Only twitch kinetics (Table 2), peak force over time (Fig. 4, limited studies were done at 20°C because it would be highly left), force-330 (Fig. 4, middle), or rate of relaxation unusual for mammalian muscle to be contracting in vivo at this cold a temperature, whereas tissue hypoxia and alter- Effects of hypoxia (37°C). Glibenclamide had no sig- ations in motoneuronal firing frequency can be seen under avariety of circumstances.
nificant effect on isometric twitch contraction and Force records were analyzed offline with use of manually half relaxation times under hypoxic conditions (Table positioned cursors displayed on the computer screen. Isomet-ric tension was measured in grams and subsequently normal-ized for each muscle strip to the average of the last three Table 2. Effects of glibenclamide on diaphragm twitches during the (predrug) baseline period. Normalization isometric twitch contraction and half relaxation was performed to minimize the confounding effects of inter- strip variability in size and hence baseline force and to reducethe influences of slight variations in dissection technique affecting baseline force. This method of normalization isconsistent with approaches used by us (24, 25, 27) and others (30) in studies of Kϩ channel blockers. Other studies of KATP blockers have normalized force to postdrug, prefatigue values (e.g., 13, 16, 28), which is similar to the present approach in ATP blockers in the concentrations used generally have minimal effects on baseline force. 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) (26; as modified from Ref. 16). During 0.1- and 5-Hz stimulation, contraction time was assessed as the amount of time for twitch force to reach its peak, and Values are means Ϯ SE from 0.1-Hz twitches immediately preced- half relaxation time was assessed as the amount of time for ing onset of the fatiguing stimulation. Values are from experiments twitch force to decay to one-half of the peak value. During A–C for normoxia at 37°C, experiment D for normoxia at 20°C, and 20-Hz trains, contraction time was assessed from the first experiments E and F for hypoxia at 37°C. Force was normalized to the twitch of the train, and relaxation time was assessed from the value for twitch force immediately before addition of drug or no drug decay in force at the end of the train.
Fig. 1. Changes in peak diaphragm force over timeduring repetitive 5- (A), 20- (B), and 100-Hz (C) stimula-tion in presence and absence of glibenclamide (100 µM)under normoxic conditions and a temperature of 37°C.
Force values are means Ϯ SE and are normalized to thevalue for twitch force immediately before addition ofdrug or no drug as described in METHODS. There were nosignificant effects of glibenclamide at 5 Hz (P ϭ 0.41), 20Hz (P ϭ 0.24) or 100 Hz (P ϭ 0.75).
2). The change in peak force over time during 5- and DISCUSSION
20-Hz stimulation was not affected significantly by Methodological issues. There are a number of agents glibenclamide under hypoxic conditions, although there was a trend for peak force to be improved by glibencla- mide during 20-Hz stimulation (Fig. 5). In contrast to previous studies of muscle contractility. Gibenclamide during normoxia, force-330 (assessed during 20-Hz was chosen for the present study on the basis of two trains) was improved significantly by glibenclamide major considerations. First, glibenclamide at the concen- during hypoxia (Fig. 6). The extent to which relaxation tration used in this study (100 µM) blocks rat skeletal rate slowed during repetitive 20-Hz stimulation was muscle KATP but not voltage-gated Kϩ channels or generally more prominent during hypoxia than during Ca2ϩ-activated Kϩ channels (17); comparable data on normoxia, and this was augmented significantly by sensitivity and specificity in rat skeletal muscle are not glibenclamide during 20- but not 5-Hz stimulation available for the other KATP blockers. However, tolbuta- mide affects muscle excitability, suggesting that it mayhave effects in addition to blocking KATP (5). Thus it wasfelt best to pick the agent for which specificity for KATPwas best established in rat skeletal muscle. Second,glibenclamide has been used in the majority of previousstudies examining muscle fatigue and KATP. Amongeight studies, six used glibenclamide (6, 12–14, 16, 30),two used glyburide (5, 28), and one study each usedphentolamine (30), ciclazindol (30), and tolbutamide(5). It is easier to compare the present data with otherdata by choosing the agent used most commonly inprevious studies (glibenclamide) rather than anotheragent (e.g., tolbutamide, glyburide, ciclazinol).
Light and French (17) examined the sensitivity to glibenclamide of KATP reconstituted from rat skeletalmuscle. They noted a concentration for one-half inhibi-tion of open probability (Ki) of 3–5 µM and found that adose of 10–100 µM was sufficient to fully eliminatevisible channel openings. The value for Ki in rat muscleis higher than that of mouse muscle (Ki of 190 nM) (1).
Light and French (17) also found that 100 µM glibencla- Fig. 2. Effects of glibenclamide (100 µM) on ability of diaphragm to mide had no effects on voltage-gated or Ca2ϩ-activated maintain force during plateau phase within the same tetanic stimula- Kϩ channels, suggesting good specificity for K tion (force-330) during 20-Hz stimulation under normoxic conditions and a temperature of 37°C. Values are means Ϯ SE. Force-330, a sistent with studies in other tissues). A glibenclamide measure of intratrain fatigue, was determined by evaluating force of concentration of 100 µM was chosen over 10 µM in the the last contraction in the train as a percentage of the maximum present study for several reasons. First, a concentra- tetanic force of the same tetanic contraction at each time point. There tion of glibenclamide was desired that would definitely was a nonsignificant trend for glibenclamide to improve force-330(P ϭ 0.12).
block KATP so that any absent effects of glibenclamide Fig. 3. Diaphragm half relaxation time over the courseof repetitive 5- (A) and 20-Hz (B) stimulation in thepresence and absence of glibenclamide (100 µM) undernormoxic conditions and a temperature of 37°C. Valuesare means Ϯ SE. *Significant differences between gliben-clamide and no drug, P Ͻ 0.05.
on fatigue could not be attributed to a concentration clamide and glyburide in either DMSO (28, 30) or that was possibly too low. Second, the present study NaOH (6, 16). The latter was chosen for the present used muscle strips, whereas French and Light (17) study because DMSO affects free radicals and thereby studied biplanar layers; a concentration higher than muscle contractile performance and, hence, could have the minimal amount needed would ensure that an greater confounding effects than a slight increase in pH adequate concentration of drug would reach the center induced by NaOH. Control and drug-treated muscle of the muscle strip. Third, a concentration of 100 µM strips had an equal amount of NaOH added to the bath was used in the most detailed previous study of gliben- so that any potential effects of acid-base changes would clamide and muscle fatigue (which also included data on action potentials) (16) so that direct comparisons An incubation period for glibenclamide of 4 min was could most easily be made by using the same drug used in the present study. Light et al. (16) examined effects of glibenclamide (100 µM) on muscle action In the present study, glibenclamide was dissolved in potential repolarization at a temperature of 20°C. They NaOH as a stock solution before it was added to the found that action potential repolarization was slowed bath. Glibenclamide (and glyburide) do not dissolve by fatigue and that glibenclamide further slowed action readily in water or saline. Previous studies of KATP potential repolarization. Furthermore, the mean val- blockers and muscle contraction have dissolved gliben- ues of the half repolarization time after fatigue in the Fig. 4. Effect of glibenclamide (100 µM) on diaphragmduring 20-Hz stimulation under normoxic conditionsand a temperature of 20°C. Values are means Ϯ SE.
Changes in peak force (left), force-330 (middle), and halfrelaxation time (right) are indicated. Peak force wasnormalized to the value for force immediately beforeaddition of drug or no drug, as described in METHODS.
Glibenclamide had no significant effects on peak force(P ϭ 0.81), force-330 (P ϭ 0.94), or half relaxation time(P ϭ 0.36).
Fig. 5. Alterations in peak diaphragm force over timeduring repetitive 5- (A) and 20-Hz (B) stimulation inpresence and absence of glibenclamide (100 µM) underhypoxic conditions and a temperature of 37°C. Forcevalues are means Ϯ SE and are normalized to the valuefor twitch force immediately before addition of drug orno drug as described in METHODS. There were no signifi-cant effects of glibenclamide during 5-Hz stimulation,but there was a nonsignificant trend for force to improveduring 20-Hz stimulation (P ϭ 0.07).
presence of glibenclamide were the same whether the assessed by utilizing a variety of stimulation frequen- drug was applied 60 min before fatigue or 60 s before cies, ranging from 0.2 to 140 Hz (5, 6, 12, 13, 16, 28, 30).
the end of fatigue. The latter data suggest a fast rate of In addition, one study used a spontaneously breathing diffusion and a fast onset of action of glibenclamide model to test diaphragm fatigue (14), in which motoneu- (Յ60 s) in skeletal muscle tissue. Light et al. studied ronal firing frequency was not assessed but would be muscle fiber bundles with diameters of 1–1.5 mm, expected to vary among motor units and over time.
which is the same size used in the present study. They During muscle contraction, Kϩ efflux and Naϩ influx used a temperature of 20°C, whereas the present study and the resultant alteration in transmembranous Kϩ used a temperature of 37°C; diffusion and onset of drug and Naϩ concentration gradients may lead to sarcolem- action should be faster at the higher temperature.
mal depolarization, especially in the T tubules in which Based on these data, 4 min should be sufficiently long diffusion of ions is slower than at the outer surface of for equilibration after drug addition.
the muscle (21, 29). Much of the Kϩ efflux during Effects of glibenclamide on muscle contraction. Ef- fects of KATP blockers on muscle fatigue have been Fig. 7. Diaphragm half relaxation time over the course of repetitive Fig. 6. Effects of glibenclamide (100 µM) on ability of diaphragm to 5- (A) and 20-Hz (B) stimulation in presence and absence of glibencla- maintain force during plateau phase within same tetanic stimulation mide (100 µM) under hypoxic conditions and a temperature of 37°C.
(force-330) during 20-Hz stimulation under hypoxic conditions and a Values are means Ϯ SE. Half relaxation times were difficult to temperature of 37°C. Values are means Ϯ SE. Force-330, a measure quantify accurately when force values became very small toward the of intratrain fatigue, was determined by evaluating force of the last end of fatiguing stimulation (see Fig. 5) and hence are reported only contraction in the train as percentage of maximum tetanic force of the for the first 2 min of the 3-min stimulation period. * Significant same tetanic contraction at each time point. * Significant differences differences between glibenclamide and no drug, P Ͻ 0.05. Contrac- between glibenclamide and no drug, P Ͻ 0.05.
tion time was not affected significantly by glibenclamide (P ϭ 0.39).
contraction occurs via delayed rectifier Kϩ channels Light et al., we found a slowing of relaxation rate by (29), although KATP has been postulated to contribute to glibenclamide during fatigue produced during 20-Hz the Kϩ efflux under conditions of depleted intracellular stimulation under both normoxic and hypoxic condi- [ATP] and concommitant acidosis (8, 21). The Naϩ-Kϩ- tions. These data suggest that KATP may be activated ATPase will restore the membranous ion gradients during fatiguing stimuli but to an insufficient extent to back to normal, but at high rates of muscle contraction affect peak force production. This is consistent with a the active transport is overwhelmed (4). Thus the role previously proposed explanation for glibenclamide not of Kϩ channels in regulating muscle fatigue is believed affecting fatigue but delaying the recovery from fatigue to be most prominent during intense muscle activation.
Hence Kϩ channel blockers should improve high- The mechanism by which altering Kϩ channel conduc- frequency more than low-frequency fatigue and intra- tance affects muscle relaxation rate is unlikely to be a train more than intertrain fatigue. That one of the direct effect on either the rate of Ca2ϩ reuptake by the studies with the greatest beneficial effects of KATP sarcoplasmic reticulum or the rate of Ca2ϩ binding by blockade on fatigue used a low stimulation rate of 0.25 parvalbumin. More likely, the effects of Kϩ channels on Hz (13) is therefore surprising and may very well reflect the rate of relaxation are mediated by altering the rate other methodological differences (e.g., use of an in vivo of action potential repolarization. Normally, membrane preparation in which vascular or other systemic effects potential repolarizes very quickly during an action of glibenclamide may have contributed to the findings) potential. As a result, there is only a brief period of time compared with the other studies of KATP blockers (5, 6, during repolarization when there is continued Ca2ϩ influx while Ca2ϩ is simultaneously being taken back In the present study we found no significant effects of up by the sarcoplasmic reticulum and/or being bound to glibenclamide on fatigue during continuous 5- or 100-Hz intracellular Ca2ϩ buffers. If action potential repolariza- stimulation or on intertrain fatigue during intermit- tion is slowed (e.g., with Kϩ channel blockade), this tent 20-Hz stimulation under normoxic or hypoxic period can be prolonged, thereby slowing the rate at conditions, consistent with all of the other in vitro which intracellular Ca2ϩ concentration ([Ca2ϩ]) falls studies of glibenclamide and fatigue (5, 12, 16, 28, 30).
and hence slowing the rate of relaxation. If the degree The only in vitro study reporting an improvement of of action potential repolarization slowing is small, it intertrain fatigue with KATP blockers noted a modest may not be sufficient to affect mechanical relaxation.
improvement in fatigue with ciclazinol but not with This could explain why Light et al. (16) found action glibenclamide (30), suggesting that ciclazinol may be a potential prolongation but no slowing of relaxation more effective blocker of KATP or may have additional with glibenclamide. On the other hand, if the degree of effects in addition to blocking KATP (e.g., blocking other action potential slowing is large, either contraction or Kϩ channels). In the present study we found no signifi- relaxation time could be slowed depending on the cant effects of glibenclamide on intratrain fatigue dur- kinetics of the changes in intracellular [Ca2ϩ] relative ing normoxia (although there was a trend toward to the kinetics of actin-myosin interactions. As muscle improvement), but we found an attenuation of intra- fatigues, action potential repolarization slows and relax- train fatigue during hypoxia. The former finding (nor- ation rate slows. Under these circumstances, effects of moxic conditions) is consistent with two previous stud- Kϩ channel blockers on rate of relaxation may become ies (5, 16), neither of which, however, examined more manifest, as was found for glibenclamide in the intratrain fatigue under hypoxic conditions. The pres- present study. This is consistent with previous studies ent finding of glibenclamide significantly attenuating of the Kϩ channel-blocking aminopyridines, which do only intratrain fatigue and only during hypoxia sug- not slow relaxation rate in nonfatigued muscle but gests that the contribution of KATP to fatigue is small markedly augment slowing of relaxation rate as muscle and is limited to conditions expected to lead to profound undergoes fatiguing contractions (25, 26).
ATP depletion and/or intracellular acidosis.
Effects of KATP blockers have been assessed at 20°C The rate of muscle relaxation slows with fatigue and (5, 16), 30°C (28), or 37–38°C (6, 12–14, 30). Studies at especially does so under hypoxic conditions (10, 11, 16, 20°C utilized frog muscle, whereas studies performed 19, 26). Two previous studies have found that glyburide at 30–38°C utilized mammalian muscle so that the and glibenclamide slow the rate of action potential influence of temperature on muscle contractile re- repolarization in resting and fatigued muscle (5, 16).
sponses to KATP blockers cannot be inferred directly Surprisingly, the rate of muscle relaxation was not from previous work. Of note, however, is that both of found to be affected by glibenclamide in either resting the studies at a cool temperature found no effect of KATP or fatigued muscle in a previous study despite changes blockers on fatigue, whereas the studies at warmer in action potential repolarization rate (16). Data on temperatures have noted variable effects of KATP block- muscle relaxation rate were not provided for glyburide ers on fatigue. Ion channels are very sensitive to (5), nor have other studies of glibenclamide and fatigue temperature, with rates of activation and deactivation reported values for rate of muscle relaxation. The having especially high values for Q10 compared with present data concur with those of Light et al. (16), who peak current; furthermore, values for Q10 may vary as a found that that KATP blockade does not significantly function of membrane potential (see, e.g., Refs. 20, 23).
alter rate of relaxation of resting muscle. In contrast to In the present study of 20-Hz stimulation during normoxia, we found that at neither warm nor cold Address for reprint requests: E. van Lunteren, Pulmonary Sect.
temperature was there a significant effect of glibencla- 111J(W), Cleveland VA Medical Center, 10701 East Boulevard,Cleveland, OH 44106 (E-mail: exv4@po.cwru.edu).
mide on either intertrain or intratrain fatigue. Thissuggests that differences among previous studies re- Received 12 June 1997; accepted in final form 1 April 1998.
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