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Depolarization accelerates the decay of K+ contractures in rat skeletal muscle fibers.

The experiments examine the effects of membrane potential on the time course of K+ contractures in small bundles of rat soleus and extensor digitorum longus (EDL) muscle fibers. Control K+ contractures were induced by exposure to a 200 mmol/L K+ solution in polarized fibers with a resting membrane potential of -83 mV (3.5 mmol/L K+), while test contractures were evoked with 200 mmol/L K+ from -46 mV, after 5, 10, and 30 min in a 30 mmol/L K+ conditioning solution. The decay times of the test K+ contracture in depolarized fibers were faster than those of the control K+ contracture in both soleus and EDL. A maximum reduction of 60% in the time for the contracture to decay from 90% to 10% was seen in soleus fibers after depolarizations lasting 10 min, while a reduction of 45% was seen in the decay time of EDL fibers after a 5-min depolarization. The amplitudes of the test contractures were 30% less than control after 5-min and 10-min depolarization and 50% less than control after 30 min. Analysis of the results suggests that the kinetics of excitation-contraction coupling may be altered in damaged muscle fibers.

Animals↗

Modulation of caffeine contractures in mammalian skeletal muscles by variation of extracellular potassium.

Caffeine contractures were induced after K(+)-conditioning of skeletal muscles from pigs and mice. K(+)-conditioning is defined as the partial depolarization caused by increasing external potassium (K+0) with [K+]x[Cl-] constant. Conditioning depolarizations that rendered muscles refractory to brief electrical stimulation still enhanced the contracture tension elicited by subsequent direct caffeine stimulation of sarcoplasmic reticulum (SR) calcium release. The effects of K(+)-conditioning on caffeine-induced contractures of intact cell bundles reached a maximum at 15-30 mM K+0 and then progressively declined at higher [K+]0. Conditioning with 30 mM K+ for 5 min, which inactivates excitation-contraction (EC) coupling in response to action potentials, both increased the magnitude of caffeine contractures 2-10-fold and shifted the contracture threshold toward lower caffeine concentrations. Enhanced sensitivity to caffeine was inhibited by dantrolene (20 microM) and its watersoluble analogue azumolene (150 microM). These drugs decreased caffeine-induced contractures following depolarization with 4-15 mM K+ to 25-50% of control tension. The inorganic anion perchlorate (CIO-4), which like caffeine potentiates twitches, increased caffeine-induced contractures approximately twofold after K(+)-conditioning (> 4 mM). The results suggest that CIO-4 and dantrolene, in addition to caffeine, also influence SR calcium release either directly or by mechanism(s) subsequent to depolarization of the sarcolemma. Moreover, since CIO-4 is known to shift the voltage-dependence of intramembrane charge movement, CIO-4 may exert effects on the transverse-tubule voltage sensors as well as the SR.

Animals↗

Collagen fiber sliding during ligament growth and contracture.

It is hypothesized that the sliding of collagen fibers past one another plays an important role in changes of ligament length during growth or contracture. To explore this possibility, we used the fluorescent dye dichlorotriazinyl fluorescein to stain collagen fibers perpendicular to their orientation in a rat medial collateral ligament model. Growth, contracture, and control models (with rats weighing 50-75 g in the first and 500-600 g in the latter two groups) were studied. In the contracture model, the medial collateral ligament was transected distally. Marking sutures were used to verify the presence of growth or contracture in each medial collateral ligament. Fluorescence photomicrography after 2 weeks demonstrated stained collagen fibers protruding from either side of the original mark as one would expect, in either growth or contracture, if the fibers slid past one another and away from their initial location during changes in length. By measuring the initial and final widths of the growth and contracture model marks and correlating them to controls that had minimal growth (rats grow throughout their life) and were free of contracture, we have provided evidence that collagen sliding plays a significant role in changes in ligament length.

Animals↗

Potassium and caffeine contractures of mouse muscles before and after fatiguing stimulation.

To assess the impairment of muscle membrane excitation, excitation-contraction (E-C) coupling, and contractility during muscle fatigue, we monitored the contracture responses of resting and fatigued muscles on exposure to high potassium and caffeine. On exposure to 140 mmol/L potassium, mouse extensor digitorum longus (EDL) developed a contracture which was 15.7% of tetanic tension before fatigue and 31.7% after fatigue, while soleus developed 59.4% contracture before and 68.8% after fatigue. Potassium causes contractures by depolarizing the muscle fiber membrane. Hence, membrane excitation is reduced in fatigued EDL and soleus. On exposure to 32 mmol/L caffeine, the contracture was 7.1% in resting EDL, 8.5% in fatigued EDL, 50.1% in resting soleus, and 43.7% in fatigued soleus. On exposure to 1 mmol/L caffeine followed by rapid cooling, the contracture was 3.0% in resting EDL, 3.2% in fatigued EDL, 21.5% in resting soleus, and 10.3% in fatigued soleus. Caffeine causes contracture by releasing Ca++ from the sarcoplasmic reticulum. Our results indicate reduced E-C coupling attributable to reduced membrane excitation in fatigued EDL, and reduced contractility in fatigued soleus.

Animals↗

Extracellular calcium dependence of contracture and modulation by serotonin in buccal muscle E1 of Aplysia.

Serotonin [5-hydroxytryptamine (5-HT)] enhances acetyl choline (ACh)-elicited contractures of Aplysia buccal muscles E1 and I5 . The possible role of external calcium in regulating the magnitude of ACh contracture in the presence and absence of 5-HT was investigated. Superfusion of E1 with zero calcium medium caused ACh contractures to fail within one to two minutes. Recovery of ACh contracture upon restoring normal medium occurred within two to four minutes. In the absence of 5-HT, ACh contracture decreased proportionally to external [Ca++] in the concentration range of 0-10 mM; however, the amount of enhancement of ACh contracture following 5-HT treatment did not decrease with external [Ca++] as long as [Ca++] was above a threshold concentration that varied from preparation to preparation. For most preparations, the enhancement of ACh contracture by 5-HT was dependent on the presence of external calcium during 5-HT treatment. Calcium influx into muscles E1 and I5 increased approximately two and a half fold in the presence of 10(-6) M 5-HT. A model in which 5-HT brings about calcium "loading" of an ACh releasable intracellular storage site is discussed.

Acetylcholine↗

Influence of divalent cations on potassium contracture duration in frog muscle fibres.

Single fibres or small fibre bundles were dissected from twitch muscles of frogs and washed in low Cl-solutions. Contractures were provoked by 122.5 mM K+. At room temperature (17-20 degrees C) the contracture duration was about 1.5 s in the absence of divalent cations and about 3 s in the presence of 2 mM Ca2+. Contractures were prolonged when Ca2+ was replaced by Ni2+ showing that inward Ca current was not the factor responsible for the contracture prolongation. K contracture duration was prolonged in the cold (3 degrees C) by a factor of about 4 in the presence of non-permeating divalent cations (Ni, Co), when 0.1 mM La3+ was applied together with 2 mM Ca2+, and in the virtual absence of divalent cations. The contractures were prolonged in the cold by a factor of 6 or more in the presence of permeant divalent cations (Ca, Sr, Ba, Mg, and Mn at 8 mM). Diffusion of divalent cations in the transverse tubules of the muscle fibres was shown to have a Q10 similar to that in free solution. It was concluded that inward current of divalent cations may shorten contracture duration by causing ionic depletion of the transverse tubules.

Animals↗

Recovery of ultrastructural changes accompanying caffeine contractures in isolated muscle fibres of the crayfish.

Reversible caffeine contractures in isolated muscle fibres of the crayfish (Astacus fluviatilis; m. extensor carpopoditi) are accompanied by swelling of the diadic cisternae of the sarcoplasmic reticulum and by constriction of the T-system tubules. The membranes of the tubules may coalesce and form pentalaminar structures. These changes in the diadic region can be found already in fibres fixed 10 s after the sudden introduction of 4 mM or 6 mM caffeine solution. The changes are completely reversible. The recovery period after a 6 mM caffeine contracture lasts 20 min. The restitution of ultrastructural changes induced by caffeine correlates well with the recovery of responsiveness to a repeated application of caffeine. The pretreatment of fibres with procaine prevents both the generation of caffeine contractures and the occurrence of changes in the ultrastructure. No changes or a very slight enlargement of diadic cisternae were found during potassium contractures of comparable size and duration to caffeine contractures. The effect of procaine as well as the restitution of ultrastructural changes after the recovery of responsiveness to caffeine support the view that the cisternal swelling is a direct consequence of the calcium releasing action of caffeine. Isolated swelling of diadic cisternae and the absence of any changes in the remaining parts of the sarcoplasmic reticulum during reversible caffeine contractures could point to the existence of functional differentiation of the respective parts of the sarcoplasmic reticulum. The absence of ultrastructural changes during potassium contractures might indicate a different source of the activating calcium for contraction and/or a different mechanism of its release.

Animals↗

Physostigmine-induced contractures in frog skeletal muscle.

Physostigmine in 15 mM concentration at pH 8.4 produces reversible contractures of up to 0.3 Po tension output in frog's whole toe muscle or in 7-10 fiber bundles of these muscles, At pH 7.2, the 15 mM physostigmine contracture output is only about 0.10 Po. The 15 mM, pH 8.4 contractures are essentially unaffected by lack of external Ca2+, complete depolarization of the fibers, detubulation by glycerol treatment, and 0 degrees C ambient temperature. These results and other evidence indicate that physostigmine produces contracture by directly releasing activator Ca2+ from the sarcoplasmic reticulum (SR). Pretreatment of muscles with 4 mM procaine reduces physostigmine's capacity to produce contracture, evidently by means of a competitive inhibition at SR sites. The above results indicate similarities between physostagmine and caffeine contractures. But the physostigmine action differs in that it is reversible, and, especially, it lacks the ability, strongly characteristic of caffeine, to sensitize a muscle to produce a rapid cooling contracture. The internal action of physostigmine requires that it be permeant, and, since it is a weak base (pKa = 8.2), this property is provided by its uncharged base. But, once internal, where the pH = 6.8, most of the drug will be protonated and it may act on the SR in this form, in contrast with caffeine which, since its pKa is about 1.0, acts on the SR as uncharged base.

Animals↗

The effect of coronary pressure on contracture and vascular perfusion in the hypoxic isolated rat heart.

The relationships among coronary perfusion pressure (0-150 cm H2O), ventricular contracture, vascular resistance, and loss of perfusion of subendocardial myocardium were studied in anoxic isolated rat hearts. Coronary flow and myocardial pH and lactate concentrations were measured during 60 minutes, and the perfusable proportion of the ventricular wall determined after 15 and 60 minutes of global, substrate-free anoxic perfusion. Myocardial contracture in similarly treated hearts was indicated by the pressure exerted on left intraventricular balloons. Decreased perfusion pressure proportionately decreased both coronary flow and the extent of perfusion, and delayed the onset of contracture. The slower development of contracture was associated with a measured increase in lactate content and fall in pH within the ventricular wall. During anoxia the subendocardial myocardium progressively lost its capacity to be perfused, commencing at the onset of ventricular contracture, and continuing to extend even after maximum contracture pressures had been developed. Increased coronary perfusion pressures accelerated the rate of development of contracture but significantly reduced the extent of the perfusion defect, probably by opposing vascular compression.

Animals↗

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients.

Administration of 5-HT2 receptor agonists induced malignant hyperthermia (MH) in susceptible pigs. Furthermore, the 5-HT2 receptor antagonist ritanserin prevented 5-HT-induced porcine MH. It has been shown that 5-HT2 receptor agonists induce marked contractures in skeletal muscle specimens from MH susceptible (MHS) but not in specimens from normal patients. The purpose of this study was to investigate the effects of ritanserin on halothane-induced contractures in muscle specimens from MHS patients. Twenty-five patients aged 8-56 years (29.5+/-13.6) classified as MHS by the in vitro contracture test (IVCT) with halothane and caffeine according to the protocol of the European MH Group participated in this study. Muscle specimens were pretreated with ritanserin 10 micromol/l (n= 14), 20 micromol/l (n=14) and 100 micromol/l (n=12) for 10 min and subsequently halothane was added incrementally (0.11-0.22-0.44 mmol/l) to the tissue bath as described in the European MH protocol. The results of the halothane contracture test were used as control. Following administration of halothane, muscle contractures reached a maximum of 16.9+/-4.2 mN. Ritanserin led to a significant inhibition of halothane-induced contractures in MHS muscles. Following pretreatment with ritanserin, halothane-induced contracture maximum was significantly smaller with 7.5+/-3.1 mN after 10 micromol/l ritanserin, 4.9+/-1.5 mN after 20 micromol/l ritanserin and 0.5+/- 0.2 mN after 100 micromol/l ritanserin than without pretreatment. Administration of ritanserin induced at all concentrations a decrease in muscle twitch height. Increase in muscle twitch following halothane was reduced in a concentration-dependent manner by ritanserin. The presented findings indicate that 5-HT might be involved in the mechanisms of halothane-induced MH in humans. Further studies have to determine the pathophysiological role of the 5-HT system in MH, and whether ritanserin could be an alternative for treatment or prevention of halothane-induced MH.

Adolescent↗

The role of enzyme activity and charge properties on the presynaptic neurotoxicity and the contracture-inducing activity of snake venom phospholipases A2.

Two toxic phospholipases A2, caudoxin from Bitis caudalis venom and the basic phospholipase A2 from Naja nigricollis venom, were selected for a study of the contribution of enzyme activity and charge properties to the presynaptic neurotoxicity and the contracture-inducing activity of the enzyme. Reducing catalytic activity by lowering the incubation temperature or by substitution of Sr2+ for Ca2+ in the bathing medium causes a significant prolongation of the time to neuromuscular block by caudoxin, but does not change the contracture-inducing activity of Naja nigricollis basic phospholipase A2. In the chick muscle pretreated with heparin, the latter enzyme fails to evoke contracture, whereas the presynaptic neuromuscular blocking action of caudoxin remains little affected. Histidine-modified Naja nigricollis enzyme, which has lost 95% of its enzyme activity, retains considerable ability to induce contracture and to abolish indirectly evoked contraction, while lysine-methylated enzyme, which loses only 10% of its enzyme activity, almost completely loses its ability to evoke muscle contracture. It is concluded that enzyme activity is important for the presynaptic effects of caudoxin, but not for the contracture-inducing action of the Naja nigricollis enzyme. In the latter enzyme certain easily methylated lysine residues are critical for its ability to induce muscle contracture.

Animals↗

Carbachol contracture of stomach smooth muscle of the newt in calcium-free solution.

A small muscle preparation of stomach circular muscle of the newt responded to carbachol (CCh) with a phasic contracture. At 20 degrees C, in Ca-free Ringer solution (+1 mM EGTA), the amplitude of CCh contracture was very rapidly inhibited to less than 10% of that in normal Ringer solution (1.8 mM Ca). The amplitude of this CCh contracture was markedly enhanced with increasing [K]0. CCh contracture in Ca-free Ringer solution was also enhanced after K contracture was induced once in the presence of 1.8 mM Ca, followed by soaking in normal Ringer solution. The amplitude of this enhanced CCh contracture persisted up to about 5 min, following rapid decrease to about 70%, and then gradually decreased to a steady level in Ca-free Ringer solution. This decrease in amplitude was prevented by increasing [K]0 during soaking in Ca-free solution; even when the temperature was elevated from 20 to 35 degrees C during the periods of soaking in Ca-free solution, CCh contracture was inhibited only by about 20% in Ca-free high K solution, whereas in Ca-free or Ca-free low Na (Tris) Ringer solution it was inhibited by more than 50%.

Animals↗

Effect of cyanide and verapamil on sodium-free contractures in the frog heart.

Sodium-free contractures were studied in myocardial strips from R. pipiens with extracellular sodium (Na0+) replaced by choline chloride and extracellular calcium (Ca20+) varied with EGTA buffer. At calculated Ca02+ below 2.8 X 10(-7) mol/l, no contracture occurred in most of the experiments, even in the presence of cyanide. When Ca02+ was above 2.8 X 10(-7) mol/l, relatively short tension transients of up to 80 sec duration could be avoided if the myocardial strip was previously equilibrated for 20 min in a Na+-Ca2+-free solution. Instead, contractures developed slowly within one to several hours. The maximum contracture was dependent on Ca02+ in a dose-response-like pattern. The time-course of contracture development was not affected by verapamil, but KCN significantly increased the rate of resting tension increase. In solutions with normal Na+-Ca2+ content and even in a Na+-Ca2+-free milieu, the cellular ultrastructure was normal. Development of contracture after addition of Ca2+ to the Na+-free solution was combined with ultrastructural damage of the ventricular strip. It is concluded that Na+-free contractures depend on transsarcolemmal net-Ca2+ uptake as a sum of Na-Ca-exchange-dependent Ca2+ uptake and active sequestering of intracellular free calcium Ca2+ mediated by sarcolemmal and probably intracellular Ca2+-ATPases. The negative inotropic effect of the Ca blocker verapamil seems not to be mediated by the Na-Ca exchange.

Animals↗

Slow sodium-free contractures in the frog heart mediated by the sodium-calcium exchange.

1. Sodium-free contractures were studied in myocardial strips from R. pipiens when extracellular sodium (Na+o) was replaced by choline chloride and extracellular free calcium (Ca2+o) was defined with EGTA-buffer. 2. Resting membrane potentials (RMP) were normal in sodium-free solutions with Ca2+o calculated below 1.0 x 10(-9) mol/l. 3. When Ca2+o was subsequently increased from zero to 1.0 x 10(-3) mol/l Na+-free contractures developed slowly with unchanged RMP even at maximum contracture, at which the intracellular ultrastructure is grossly altered. 4. The contractures developed significantly faster in the presence of 3 x 10(-6) mol/l ouabain. 5. In sodium-free solutions La3+ did not influence Ca2+-dependent contractures, apart from causing an increase in time to maximum contracture. 6. It is concluded that sarcolemmal integrity is maintained in frog myocardium treated initially with Na+/Ca2+-free solutions and then with Na+-free medium containing 1 mmol/l Ca2+. 7. Our experiments indicate that sodium-free, Ca2+o-dependent contractures are mediated by the Na+/Ca2+-exchange, operation at higher rates when Na+i is increased. La3+ (1 mmol/l) probably does not compete with Ca2+ at extracellular binding sites of the exchanger. 8. The Na+/Ca2+-exchange may under certain experimental conditions be able to increase Ca2+i to cytotoxic concentrations.

Animals↗

The use of subcutaneous pedicle multiple rhomboid flaps in the treatment of long postburn scar contractures.

The subcutaneous pedicle rhomboid flap is a relatively new technique in the treatment of linear, wide or quadratic postburn scar contractures with two or more contracture lines. The effectiveness of the rhomboid flap depends on lengthening the contracture band by relaxation incisions and closing the emerged defect by suturing the rhomboid flap in V-Y and Y-V advancement. The technique is simple, efficient and versatile. The broad subcutaneous pedicle of the flap is very reliable and postoperative flap necrosis is rare. Clinical results show that the gain in length provided by a single rhomboid flap ranges from 75-90%. However, the technique may not be efficient enough to release the whole band in cases of long contracture bands. Therefore, a new design of rhomboid flaps, called "multiple rhomboid flaps", may be needed. Twelve patients (aged 3-40 years) with long linear and wide scar contractures were successfully treated with subcutaneous pedicle multiple rhomboid flaps. Multiple consequent or adjacent rhomboid flaps were applied in the upper extremity (in nine patients), trunk (in seven patients), and lower extremity (in two patients). Complete relaxation and elongation of the contracture bands were achieved in all of the cases and all rhomboid flaps healed uneventfully. The results were functionally and cosmetically successful. The application of rhomboid flaps in this consequent and adjacent fashion is a new concept. Clinical results prove that the technique is versatile and effective in the release of long potstburn scar contractures. Since distortion of the surrounding skin or displacement of anatomical landmarks is not seen with the technique, color and texture matches are perfect. Designing and performing multiple rhomboid flaps is very simple and the operation time is short. As no undermining is carried out in the technique, the flaps are more reliable than commonly used multiple Z-plasty.

Adolescent↗

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine.

BACKGROUND AND OBJECTIVE: The phosphodiesterase-III (PDE-III) inhibitor enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of enoximone or caused by inhibition of PDE-III remained unclear. Therefore, the effects of the PDE-III inhibitor amrinone in porcine MH normal (MHN) and MHS skeletal muscles were investigated. METHODS: MH-trigger-free general anaesthesia was performed in eight MHS and eight MHN swine. The MH status of the swine was determined by detection of the Arg615-Cys point mutation on chromosome 6 indicating MH susceptibility. Skeletal muscle specimens were excised for the in vitro contracture tests with amrinone. Amrinone was added cumulatively every 5 min to muscle specimens in order to obtain organ bath concentrations between 20 and 400 micromol L(-1). The in vitro effects of amrinone on muscle contractures and twitches were measured. RESULTS: Amrinone-induced contractures in all skeletal muscle preparations. MHS muscles developed contractures at significantly lower bath concentrations of amrinone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 80, 100, 150, 200 and 400 micromol L(-1) amrinone. Muscle twitches remained unchanged up to and including 200 micromol L(-1) amrinone. CONCLUSIONS: Inhibition of PDE-III in general elicited higher contractures in MHS than in MHN muscles. Therefore, a contribution of PDE-III and the cyclic adenosine monophosphate (cAMP) system in the pathophysiology of MH must be suspected.

3',5'-Cyclic-AMP Phosphodiesterases↗

In vitro muscle contractures induced by halothane and suxamethonium. II: Human skeletal muscle from normal and malignant hyperthermia susceptible patients.

The role of lipolysis in halothane-induced contractures of human skeletal muscle was examined using three inhibitors of phospholipase A2 (PLA2) activity (quinacrine, spermine and indomethacin) and exogenously administered PLA2. In addition, we examined the effects of the same PLA2 inhibitors on contractures induced by halothane in combination with suxamethonium. The studies were conducted on directly stimulated muscle strips isolated from biopsies from patients diagnosed as MH susceptible, or not susceptible, by the halothane contracture test. The liberation of fatty acids from skeletal muscle homogenates was examined to determine whether PLA2 activity might be increased in MH susceptible patients. The three PLA2 inhibitors antagonized halothane-induced contractures of muscle from MH susceptible patients as well as induction of contractures by suxamethonium and halothane. Pre-exposing preparations that were previously unresponsive to halothane to bee venom PLA2 caused the muscle strips to respond with contractures upon subsequent challenge with halothane, but not with suxamethonium. Free fatty acid production during an in vitro incubation of skeletal muscle homogenates was greater in preparations from MH susceptible patients than in those from patients who were not susceptible. These results suggest that excess liberation of fatty acids may be involved in halothane-induced contractures of muscle from MH susceptible individuals, in the synergism observed between halothane and suxamethonium, and in human MH.

Disease Susceptibility↗

Multicentre evaluation of ryanodine contracture testing in malignant hyperthermia. The European Malignant Hyperthermia Group.

A common protocol for in vitro contracture testing using the plant alkaloid ryanodine has been used by the European Malignant Hyperthermia Group since 1993. This protocol describes a test using I mumol/litre of high purity ryanodine (98%) added as a single bolus dose. The main aim of this study was to compare the results obtained with this test between laboratories with a view to assessing the validity of adopting common diagnostic end-points for use in future collaborative studies. In order to do this it was first necessary to determine the optimum cut-off values of the end-points for discriminating between patients diagnosed as susceptible or not to malignant hyperthermia. The end-points under evaluation were expressed in terms of time after application of ryanodine at which a certain degree of contracture develops. In this study, four end-points were investigated: time to initial contracture development (Ot); time to development of a 10-mN contracture (10t); time from addition of ryanodine to when baseline tension exceeds pre-drug tension (0tp); and time for contracture to reach 10 mN above pre-drug baseline tension (10tp). This protocol was developed initially and used by three investigating centres and the initial assessment of the end-points and their discriminatory ability was made using the first 100 patients from each of centres 1 and 2, and the first 90 patients from centre No. 3. Optimal cut-off values for each of the end-points were determined using logistic regression analysis. Discriminatory ability was improved by combining the Ot and 10t end-points (P < 0.05) but not significantly by combining the 0tp and 10tp end-points. Both methods of categorization were highly sensitive and specific compared with the current standard diagnostic tests. Results from eight additional diagnostic centres which have used the ryanodine contracture test more recently, while indicating that susceptible and normal individuals can be distinguished within a single laboratory, produced a level of variability between testing centres for the ryanodine contracture test that is incompatible with the use of common cut-off values. Possible causes for this variability between laboratories are discussed.

Evaluation Studies as Topic↗