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PubMed2004

Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia.

BACKGROUND: The diagnosis of susceptibility to malignant hyperthermia (MH) is currently performed on muscle biopsies subjected to halothane-caffeine in vitro contracture tests (IVCTs). There is a consensus on our need to improve the diagnostic potential of IVCTs if we are to maximize the information available for research and diagnosis in MH. This study was designed as a pilot comparative study and we aimed at comparing the ryanodine test and new tests using a combination of ryanodine, halothane and caffeine. METHODS: One hundred and thirty-two subjects (52 MHS and 80 MHN) were included in this study and new IVCTs were performed in additional muscle biopsy specimens. The contracture time-course was compared considering the onset time of contracture (OT) and the time to reach a 10 mN contracture (10T). Cut-off values were determined using ROC analyses. RESULTS: For the ryanodine test, sensitivity and specificity calculated for OT were 84.6% and 90.4%, respectively, and were better than those obtained using 10T. Combined tests using either caffeine and ryanodine or halothane and ryanodine did provide higher sensitivities (from 85.3 to 93.9%). A better specificity was only observed for the IVC tests combining halothane (cumulated) and caffeine both with ryanodine (93.9% for both). The largest sensitivity was observed when halothane was used as a bolus and combined with ryanodine. The specificity was always larger with the combined tests as compared to the test using ryanodine alone (from 79.1 to 90.9%). This superiority was confirmed, at least in part, when comparing genetic investigations and the results of new tests in a subgroup of subjects. CONCLUSIONS: This pilot study showed a clear diagnostic potential for new IVC tests combining halothane, the triggering agent of MH, and ryanodine acting at the calcium release channel, and should be considered as a first step in the investigation of combined tests.

Anesthetics, Inhalation↗
PubMed1983

The control of muscle contracture by the action of dantrolene on the sarcolemma.

Although dantrolene reverses the muscle contracture seen during a malignant hyperpyrexia (MH) crisis, its site of action is not known. It has been inferred from previous work that the major abnormality in MH is in the sarcoplasmic reticulum, and that dantrolene must act on this organelle. In the present study the ability of dantrolene to control drug-induced muscle contraction was tested. The drugs were chosen because their sites of action were known for inducing contracture. Dantrolene had no effect on contractures induced by 2:4 dinitrophenol, exerted only a minor effect on caffeine contractions, but reduced significantly the contracture produced by K+. It is postulated that the major action of dantrolene is on the sarcolemma, which may be the site of the MH abnormality.

Animals↗
PubMed1995

Modulation of ryanodine-induced contractures in human skeletal muscle pretreated with dantrolene.

Dantrolene seems to be the causal therapy in malignant hyperthermia (MH) crisis but the complex mechanisms of MH and dantrolene therapy are still not fully understood. The influence of dantrolene on ryanodine-induced contractures has been reported in animal studies only. In the present study 20 patients from 17 families were tested for MH using the protocol of the European Malignant Hyperthermia Group. In addition ryanodine-induced contractures were evaluated following bolus application of 10.0 mumol.l-1 ryanodine. After pretreatment with 1 mumol.l-1 dantrolene ryanodine-provoked contractures developed significantly later in MHS (15.8 +/- 1.8 min) and MHN (46.0 +/- 4.2 min) muscle specimens than after ryanodine alone (MHS 4.8 +/- 0.7 min. (MHN 13.7 +/- 0.9 min). They were no longer observed in either group after pretreatment with 5 mumol.l-1 dantrolene. We conclude that dantrolene is able to attenuate ryanodine-induced contractures dose-dependently, and therefore it is speculated that dantrolene could specifically act at the ryanodine receptor binding site.

Adolescent↗
PubMed1988

Potassium contractures in the mouse diaphragm: regional variation in the multiphasic response.

1. Submaximal potassium-induced contractures were studied in isolated mouse hemidiaphragms (HD) and compared with extensor digitorum longus (EDL) and soleus. 2. In the HD, the contracture was triphasic: an initial small, fast phase followed by a larger slow phase, and a late phase which was seen on prolonged exposure. 3. Costal segments of the HD responded to elevated potassium with a larger fast phase, while dorsal or ventral segments produced a larger slow phase. 4. In calcium-free solution, the fast phase appeared to be unaffected, while the slow phase was potentiated and its time course abbreviated. The late phase was greatly attenuated or abolished. 5. In the soleus, but not the EDL muscle, contracture amplitude in calcium-free solution was potentiated and the time course was shortened. 6. The characteristics of potassium-induced contractures of both the soleus and EDL muscles are to be seen in the response of the hemidiaphragm, but there is a regional variation in their proportional contribution which suggests a heterogeneity in diaphragm composition.

Animals↗
PubMed1996

HOE 694 affords protection versus veratrine contractures in rat atria by Na+ channel blockade.

We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na(+)-H+ exchange, against veratrine-induced diastolic contractures and action potentials recorded in rat isolated left atria. Concentration-dependent protective effects against veratrine-contractures, in the absence of negative inotropic responses, were observed with HOE 694 (IC50 = 20.1(7.6-27.0) microM, n = 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with amiloride itself. Concomitant Na(+)-H+ exchange blockade by a high concentration of amiloride (100 microM) failed to significantly modify the protective effects of HOE 694. HOE 694 decreased Vmax significantly at 10 microM (166.7 +/- 21 vs 154.7 +/- 20 V/s, P < 0.05, n = 6) without any effect on resting potential or action potential duration. High concentrations (100 microM) of HOE 694 further decreased Vmax and increased action potential duration. The protective effects of HOE 694 were compared with three of the class 1 antiarrhythmic agents, quinidine, lidocaine and flecainide against veratrine contracture. These Na+ channel blockers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine contractures at concentrations which presumably affect Na(+)-H+ exchange. However, the mechanism by which HOE 694 affords protection is apparently mediated by class 1-type Na+ channel blockade.

Action Potentials↗
PubMed1989

Comparative effects of bepridil, its quaternary derivative CERM 11888 and verapamil on caffeine-induced contracture in ferret hearts.

1. The effects of bepridil, its quaternary derivative: CERM 11888 (methyl-pyrrolidinium bromide) (10(-7)-10(-5) M), and verapamil (10(-7)-10(-6) M) were compared on caffeine-induced contracture of isolated ventricular trabeculae of the ferret. 2. Bepridil diminished the amplitude of contracture in a concentration-dependent fashion, and this effect was significantly different from that of CERM 11888 which, like verapamil, only reduced the amplitude at the highest concentration used. 3. Bepridil (10(-6) M) significantly shortened the time to peak tension and accelerated the relaxation phase of contracture. This latter effect was different from that of CERM 11888. Verapamil (10(-6) M) also tended to accelerate the relaxation phase. At 10(-5) M these actions of bepridil on the time to peak and relaxation tended to reverse. 4. At all concentrations bepridil and verapamil reduced the rate of repriming of contracture and this effect of bedpridil was significantly different from that of its quaternary derivative which only showed a significant effect at 10(-5) M. 5. These results demonstrate a clear intracellular effect of bepridil in the ferret heart. Verapamil and CERM 11888 had only weak intracellular effects even at high concentrations. 6. Analysis of the results suggests that the main sites of action of bepridil in this model are the sarcoplasmic reticulum and one or two calcium compartments in the sarcolemma.

Animals↗
PubMed1990

Effects of putative neurotransmitters and related drugs on withdrawal contractures of guinea-pig isolated ileum following brief contact with [Met5]enkephalin.

1. Brief exposure for 2 min of guinea-pig isolated ileum to [Met5]enkephalin (MEnk) and noradrenaline has been shown previously to produce withdrawal contractures on washout of the agonist or addition of naloxone (MEnk) or phentolamine (noradrenaline). 2. The present study was undertaken to investigate firstly, whether other putative neurotransmitters and/or related drugs which inhibit transmitter release also produced withdrawal responses following 2 min contact with the ileum and secondly, whether they affected the opioid withdrawal response. 3. Adenosine (1-5 microM), but not U-50,488H (1-5 microM), somatostatin (0.01-5 microM), ocreotide (1-5 microM), baclofen (1-25 microM) or dopamine (5, 50 microM), produced a contracture on washout following 2 min contact with the ileum. The adenosine (5 microM) washout contracture, in common with MEnk and noradrenaline washout contractures, was inhibited by the substance P antagonist, spantide (10 microM). 4. Added 30 s before washout at a concentration of 5 microM, noradrenaline, U-50,488H, adenosine, somatostatin and ocreotide significantly inhibited the washout withdrawal response following 2 min contact of the ileum with MEnk, 1 microM. A higher concentration of baclofen, 250 microM, also inhibited this response. 5. The naloxone (1 microM)-precipitated withdrawal response following contact of the ileum with MEnk, 1 microM, for 2 min, was inhibited only by noradrenaline (5 microM) and U-50,488H (5 microM). 6. It is concluded that during naloxone-precipitated opioid withdrawal an additional population of enteric motor neurones is recruited which is not involved in the washout withdrawal response and these neurones have less diversity of presynaptic receptors mediating inhibition of transmitter release than cholinergic motor neurones.

Animals↗
PubMed1993

Withdrawal contractures of guinea-pig isolated ileum after acute activation of kappa-opioid receptors.

1. The present study was undertaken to investigate firstly whether a brief exposure for 5 min of guinea-pig isolated ileum to the kappa-opioid agonist, U-50,488H produced a withdrawal contracture on addition of naloxone and secondly to ascertain whether the response was due to the activation of kappa-opioid receptors. 2. Naloxone (10(-6) M) did not elicit a response in preparations exposed to U-50,488H (5 x 10(-7) M-2 x 10(-6) M). However, after exposure to U-50,488H (5 x 10(-7) M), naloxone (10(-6) M) produced a strong contracture if the agonist was washed out 1 min before the addition of the antagonist. 3. The addition of naloxone (10(-6) M) to the ileum preparation exposed to U-50,488H (10(-7) M or lower) caused a response of similar intensity irrespective of whether the agonist had been washed out. 4. The selective kappa-opioid antagonist, nor-binaltorphimine (2.7 x 10(-9) M and 2.7 x 10(-7) M), injected before the opioid agonists, prevented the naloxone-induced contracture after exposure to U-50,488H (8 x 10(-8) M) but did not affect the contracture after exposure to morphine (5 x 10(-7) M). 5. Nor-binaltorphimine (2.7 x 10(-9) M) caused a contraction of the ileum preparation when injected 5 min after exposure to U-50,488H (8 x 10(-8) M) but not after morphine (5 x 10(-7) M). 6. The alpha 2-adrenoceptor agonist, clonidine (3 x 10-8 M) and the calcium channel blocker, nifedipine(3 x 10-8 M), injected 1 min before naloxone, blocked the ileum contraction to naloxone after exposure to U-50,488H (8 x 10-8 M). The results demonstrate that the stimulation of Kappa-opioid receptors can induce a similar dependence in guinea-pig ileum to that produced by activation of micro receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Transmitter-mediated local contracture of the endplate region of the focally innervated mouse diaphragm treated with anticholinesterase.

1. Local contraction of the endplate region in response to nerve stimulation was studied in isolated mouse diaphragms. In normal preparations, muscle contractions involved the whole length of the muscle fibre with rise and decay times in the order of tens of ms whether evoked with a single or train of pulses. 2. When acetylcholinesterase was inhibited with neostigmine, tetanic stimulation produced a twitch-like phasic contraction and a delayed tonic contracture. A brief train of pulse (10 ms, 300 Hz) was enough to trigger a full size tonic contracture which reached an amplitude about one tenth that of control tetanus and had a duration of about 4 s. 3. Tetanic stimulation evoked a non-propagating prolonged depolarization at the endplate region lasting for about 1 s following a few muscle action potentials. 4. mu-Conotoxin, a specific inhibitor of muscle Na+ channel, selectively abolished the phasic contraction and the muscle action potentials leaving the tonic contracture and the prolonged depolarization unaffected. 5. Both the tonic contracture and the prolonged depolarization were highly sensitive to blockade by tubocurarine (IC50 0.05-0.1 microM) and vesamicol (1 microM, an inhibitor of packaging acetylcholine into synaptic vesicles), were attenuated by increasing Ca2+ concentration and were prolonged by decreasing Ca2+. 6. The results suggest that prolonged activation of endplate nicotinic receptors by endogenously released transmitter can produce substantial contractions of the endplate region when acetylcholinesterase are inhibited. The source of Ca2+ for the contraction seems to come mainly from intracellular stores.

Action Potentials↗
PubMed1988

The effects of fructose 1,6-diphosphate, caffeine and dantrolene sodium on suxamethonium-induced contractures in denervated rat skeletal muscle.

Previously unidentified forms of suxamethonium-induced contractures have been investigated in chronically denervated rat extensor digitorum longus (EDL) muscle at 20 degrees C. Contractures were assigned to groups 1-6 on the basis of the peak tension (Tp1) during 0-10 min exposure to the drug (3.0 x 10(-5) M), (7.0 x 10(-6) M), and (3.5 x 10(-6) M) and the subsequent retention, increase, or decrease in tension (Tp2), during the further 10 min. It is proposed that four stages exist in the development of contractile changes at 1-7, 8-35, 36-70 and 70-130 days after denervation (DPD) and that contractility is lost at 147 days after denervation. Initial changes, although present in EDL muscles in group 1 at 2.0 DPD s.d. +/- 1 (n = 7) in response to the drug (3.0 x 10(-5) M), were more apparent in EDL muscles in group 2 which were identified at 5.5 DPD s.d. +/- 1.6 (n = 7) by an excessive contracture response (Tp2) to the drug (3.0 x 10(-5) M), 18.3 mN s.d. +/- 10.6. At 5.0 DPD s.d. +/- 2.7 (n = 5) contracture tension (Tp2) was commensurate with membrane depolarization, 13.1 mN/33.1 mV, but residual tension increased to 23.3 mN during the Krebs wash (80 min) whilst membrane depolarization decreased to 9.2 mV. Also, at 4.3 DPD s.d. +/- 2.3 (n = 5) tension (Tp2) increased significantly (P less than or equal to 0.05) in the presence of caffeine (4.1 x 10(-3) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

The effects of pH on the sodium-withdrawal contractures evoked from frog atrial trabeculae.

Contractures can be evoked from frog atrial trabeculae by raising extracellular pH in Na-free fluid after the spontaneous relaxatin of the tension evoked by removing extracellular Na+. These alkalinity contractures are unaffected by local anaesthetics but are absent following a brief perfusion with Ca-free fluid but are partially inhibited by local anaesthetics. Perfusion by solution containing a high Pco2 fails to induce contractures. The relationship between [Na]0 and tension is altered by changing extracellular pH; acidic fluids below pH 6.0 reduce tension and alkaline fluids increase tension over the whole range. NH4Cl has the same effect as alkaline fluids while CO2-containing fluid has no effect. These results can be interpreted if the effects of variation of extracellular pH, on Na-withdrawal contractures, are mediated by changes in intracellular pH which in turn affect the Ca-sensitivity of the contractile proteins.

Ammonium Chloride↗
PubMed1984

The measurement of intracellular sodium activity and its relationship to the action of calcium ions upon the low-sodium contracture in frog atrial trabeculae.

If the Na concentration of the solution bathing a frog atrial trabecula is reduced a contracture rapidly develops and then relaxes spontaneously. If the Ca concentration of the low-Na solution is raised during this relaxation a further contracture may develop. The amplitude of this Ca-addition contracture depends in a complex manner upon [Na]o. It also shows a time dependence which is similar to the rate of spontaneous relaxation and the time course of the fall in aiNa as measured by ion-sensitive micro-electrodes. These observations are discussed in terms of transmembrane ion movements, the processes occurring during spontaneous relaxation and a possible compartmentalization of both intracellular Ca and Na ions. A relationship between [Na]i and [Na]o is derived from the contracture data that compares well with direct measurements made using ion-sensitive micro-electrodes.

Animals↗
PubMed1967

Actions of calcium and certain multivalent cations on potassium contracture of guinea-pig's taenia coli.

1. Using a calcium buffer system, the effect of severe calcium lack on the shape of K-contracture of the guinea-pig's taenia coli was studied. Under conditions of calcium lack, the initial phasic response was preferentially affected and it disappeared completely at concentrations below 10(-7)M, while the ensuing tonic response persisted, though considerably diminished in size, even at the concentration of 10(-8)M.2. In calcium-free media, various multivalent cations, which according to Frank (1962) can support the K-contracture of a skeletal twitch muscle fibre in calcium-free solution, augmented the remaining tonic response, but did not restore the phasic response, when it was eliminated in calcium free environment.3. When K-contractures were induced in normal calcium media, these cations produced, in contrast, an abolition of the phasic response together with a partial depression of the tonic phase. They also inhibited a part of the fully developed contracture. The last effect was no longer obtainable in calcium-free media.4. It is concluded that the phasic response and a part of the tonic response of taenia coli depend upon the extracellular calcium for their initiation (and also for maintenance of tension in the case of the latter) and that the rest of the tonic response draws on a store of ;bound' calcium for its evolution.

Animals↗
PubMed1971

Ultrastructure and contractures of the pigeon iris striated muscle.

1. The ultrastructure of adult pigeon iris muscle fibres has been described with emphasis on the distribution of the sarcoplasmic reticulum (SR). Contractures due to superfusion with solutions of different [K(+)] (3-150 mM) and acetylcholine (ACh) and their modification by alteration of external [Ca(2+)] and [Mg(2+)] were studied in isolated pigeon iris.2. The arrangement of the contractile myofilaments was like that of vertebrate skeletal fibres. The SR is well developed in the I-band and sparse at the A-band level. Tubular elements (T-system) which form triads with the SR were seen at all levels of the sarcomere though usually adjacent to the A-I junction.3. K(+) contractures developed monotonically to a steady level which was maintained for the duration of the high [K(+)] superfusion. The response to a standard [K(+)] stepwise change was not altered by conditioning the preparation with various [K(+)].4. Decreasing external [Ca(2+)] from 20 mM to Ca(2+)-free (i.e. no Ca(2+) added), enhanced iris contractures at all [K(+)] and in ACh enriched solutions. The K(+) response was abolished when the iris was superfused with Ca(2+) free solution plus EDTA (2 mM) for 45 min. Increasing [Mg(2+)] had little or no effect on iris contracture.5. Reducing external [Ca(2+)] from 3 to 0.3 mM caused a reduction of 3-7 mV in resting membrane potential and an increase from 3 to 10 mM-Ca(2+) caused 3 to 7 mV membrane hyperpolarization. Muscle fibre input resistance was not affected.6. It is concluded that in the pigeon iris, Ca(2+) required for contractile activation is obtained from internal stores, that membrane potential determines the degree of contractile activation and that the maintenance of the contracture is dependent on the failure of the Ca(2+) releasing mechanism to inactive. In addition, it is speculated that because the iris muscle has only sparse SR at the A-band level of the sarcomere, there may be slow Ca(2+) reaccumulation.

Acetylcholine↗
PubMed1972

Influences of sodium and calcium on the recovery process from potassium contracture in the guinea-pig taenia coli.

1. In the guinea-pig taenia coli, influences of Na and Ca ions on the recovery process from the K contracture were investigated. In the absence of Na ion (sucrose-Krebs solution), the K contracture did not recover when the external K (143 mM) was returned to the normal concentration (5.9 mM), although the membrane was repolarized to normal resting potential.2. After reducing the external K concentration to normal, the addition of Na rapidly terminated the contracture. About 5 mM-Na was enough to produce the relaxation, but the rate of relaxation was slower the lower the Na concentration.3. Lithium could substitute for Na in the relaxation, but Tris-hydroxymethyl aminomethane could not. The possibility of a chloride contribution was excluded.4. Ouabain (2 x 10(-6) g/ml.) and K removal reduced the rate of relaxation by Na ion only slightly. Lowering the temperature also had a small effect, having a Q(10) of about 1.4. Therefore, the Na-K pump may not be involved in this process, but a physical process seems responsible.5. The contracture in K-Krebs solution and in sucrose-Krebs solution was dependent on the external Ca concentration suggesting a high Ca permeability of the membrane. When sucrose was isosmotically replaced with Mn, Mg, La or Ca ions the relaxation was produced with a relatively fast speed in the absence of external Na ions.6. These results may be explained by assuming that external Na ions are involved in decreasing the Ca permeability of the membrane and in reducing the intracellular Ca concentration by Na-Ca exchange, energy for which is supplied by Na influx. In the relaxation by polyvalent cations, suppression of the Ca permeability is probably the main factor.

Action Potentials↗
PubMed1985

Hg2+-induced contracture in mechanically skinned fibers of frog skeletal muscle.

In mechanically skinned fibers of the semitendinosus muscle of bullfrogs, we examined the role of membrane sulfhydryl groups on Ca2+ release from the sarcoplasmic reticulum (SR). Hg2+, a sulfhydryl reagent (20-100 microM), induced a repetitive contracture of skinned fibers, and this contracture did not occur in skinned fibers in which the SR had been disrupted by treatment with a detergent (Brij 58). Procaine (10 mM), Mg2+ (5 mM), or dithiothreitol (1 mM) blocked the Hg2+-induced contracture. Ag+ or p-chloromercuribenzenesulfonic acid produced similar contractures to that induced by Hg2+. We conclude that Hg2+ releases Ca2+ from SR of a skinned fiber by modifying sulfhydryl groups on the SR membrane, and suggest that the Ca2+ released by Hg2+ may trigger a greater release of Ca2+ from SR to develop tension.

Animals↗
PubMed1987

The mechanism of ryanodine action in rabbit ventricular muscle evaluated with Ca-selective microelectrodes and rapid cooling contractures.

Cellular Ca uptake and efflux in rabbit ventricular muscle was measured using double-barreled Ca microelectrodes in the extracellular space. When repetitive stimulation was stopped there was a slow loss of cellular Ca. Upon resumption of stimulation Ca was taken up by the cells. These Ca movements are thought to represent the loss of Ca from the sarcoplasmic reticulum and the cell during rest and the refilling of the sarcoplasmic reticulum during stimulation. Ryanodine (100 nM) greatly enhanced both the efflux of Ca during rest and the uptake of Ca induced by stimulation. These results are consistent with the conclusions drawn below, but they are dependent upon the interpretation that these extracellular Ca depletions are indicative of sarcoplasmic reticulum Ca movements. To examine further this process, contractures induced by rapid cooling to 0 degrees C were used as an independent assay of sarcoplasmic reticulum Ca content. These rapid cooling contractures were smaller after longer rest intervals (declining with a half time of 1.5 min). In the presence of ryanodine, the rapid cooling contracture immediately after a contraction was greater than that seen under control conditions. However, in the presence of ryanodine these rapid cooling contractures decline as a function of rest duration with a half time of about 1 s. These results suggest that in the presence of ryanodine the sarcoplasmic reticulum can still take up Ca, but that it also loses this Ca very rapidly at the onset of rest.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1990

The role of ATP in energy-deprivation contractures in unloaded rat ventricular myocytes.

Energy-deprivation contractures were investigated in unloaded rat ventricular myocytes. Application of 2 mM cyanide in the presence of 10 mM 2-deoxyglucose (metabolic blockade) led to a rapid shortening "contracture" (maximum speed 1.5 +/- 0.2% control cell length/s). Cells shortened to a constant length of 69 +/- 1.6% of the control length. Removal of cyanide caused cells to shorten further ("recontracture"), before relaxing towards the control length. Cells shortened to 57 +/- 2.0% during the recontracture. Similar behaviour was observed in zero extracellular [Ca2+]. Cells permeabilized with saponin (0.1% w/v) responded to the removal of ATP from the bathing solution, and to readdition of ATP, as intact cells did to complete metabolic blockade and its removal. In these permeabilized cells, the extent and speed of contracture shortening were similar at pCa = 7 and pCa greater than 9. When the bath concentration of ATP ([ ATP]b) was lowered to zero, shortening stopped at about 70% of the control length. However, when [ATP]b was lowered to an intermediate level (4-20 microM), cells contracted to lengths as short as 30% of the control length. Similarly, when [ATP]b was restored from zero to an intermediate concentration (4-20 microM), recontracture shortening continued without relaxation. The peak speed of this Ca2(+)-independent shortening showed a sigmoidal dependence on pMgATP (pMgATP0.5 = 4.0). Phosphocreatine (10 mM) shifted the ATP dependence of Ca2(+)-independent shortening to lower [ATP]b (pMgATP0.5 = 5.0), suggesting that gradients of [ATP] could exist between the bath and the myofilaments. Ca2(+)-independent shortening was inhibited by the chemical phosphatase 2,3-butanedione monoxime (BDM), although BDM did not relax cells from the shortened state during energy deprivation. Using a simple model, we show that the results can be explained by cross-bridge cycling occurring independently of Ca2+ over a "window" range of [MgATP] (0.1-100 microM). Therefore, when [MgATP] falls, cross-bridge cycling occurs and the cell shortens. As [MgATP] falls to very low levels ([ MgATP] less than 1 microM), shortening ceases as the rate of cross-bridge cycling declines. Recontracture occurs on restoring ATP production, because stiffness falls and Ca2(+)-independent cross-bridge cycling initially increases. As [MgATP] rises above 100 microM, Ca2(+)-independent cross-bridge cycling ceases and the cell relaxes towards the control length. We conclude that energy-deprivation contractures, and recontractures, can result from changes in [MgATP] and do not necessarily require changes in [Ca2+]i.

Adenosine Triphosphate↗