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At least 19 recordsLinked to original sources

PubMed1979

Dantrolene and suxamethonium. The effect of pre-operative dantrolene on the action of suxamethonium.

A single oral dose of dantrolene (100--150 mg) given at least 2 hr pre-operatively has been found to reduce significantly the strength of muscular fasciculations, the hyperkalaemia and the incidence of muscle pains following suxamethonium (from 56 to 4%) in a series of forty-eight patients compared with controls. The biceps EMG of the fasciculations was unchanged by dantrolene; the incidence of troublesome side effects was low (9%) and there did not appear to be any alteration in the duration of action of suxamethonium.

Adult↗

PubMed1979

The effect of dantrolene sodium on rat skeletal muscle in relation to the plasma concentration.

Dantrolene sodium is a muscle relaxant used in the treatment of spasticity. It has been shown to interfere with calcium release from the sarcoplasmic reticulum and thus to inhibit excitation--contraction coupling. The effect of dantrolene sodium on the twitch tension of the tibialis anterior muscle of the rat was measured after 2 mg/kg i.v. or 25 mg/kg orally. Plasma concentrations were estimated at maximum twitch depression and during recovery from the block. In a separate series of experiments the half-life of labelled dantrolene sodium was measured in blood plasma, skeletal muscle and heart muscle of rats. Dantrolene sodium 2 mg/kg i.v. gave a maximal block of approximately 47%, the mean dantrolene sodium concentration was then 5.8 microgram/ml. A half-life for distribution of 1.1 min and an elimination half-life of 31 min after intravenous administration were observed, elimination rate constants in skeletal and heart muscle were comparable. Recovery from the block went much slower, the half-time of the process being approximately 80 min. Dantrolene sodium 25 mg/kg orally gave a maximal block of approximately 38% at a mean plasma concentration of 3.6 microgram/ml after 14 min. The recovery was again very slow. These experiments demonstrated that dantrolene sodium acts according to a two-compartment pharmacokinetic model. There was a discrepancy between duration of effect and plasma concentration of dantrolene sodium in the rat. This suggests that the receptor for dantrolene sodium is not located in the central compartment.

Animals↗

PubMed1977

Inhibition of the intracellular release of calcium by Dantrolene in barnacle giant muscle fibres.

1. Ca movements in resting and in activated single giant muscle fibres of the barnacle were analysed before and after exposure to Dantrolene Na, a synthetic hydantoin derivative. 2. In fibres micro-injected with the photoprotein aequorin, the resting rate of light emission (resting glow) reversibly decreased upon exposure to Dantrolene. Similar results were obtained if the fibre had first been equilibrated in a O Ca-1 mM-EGTA medium. 3. The influx of 45Ca into resting muscle fibres was not modified by 35 micronM Dantrolene which also failed to significantly reduce the influx of 45Ca into muscle fibres which had been depolarized by exposure to external solutions in which K+ had been increased to 60 or 200 mM. 4. In fibres micro-injected with 45Ca, the calcium efflux was reversibly decreased by Dantrolene. This effect was still observed in O Ca medium and in O Ca-ONa medium. A possible effect of Dantrolene on the Na-Ca exchange process at the outer membrane was excluded by showing that when the direction of the Ca2+ movement was inverted in aequorin-loaded fibres by the sudden removal of Na+ from the external medium, a marked increase in the resting glow was recorded which was not affected by exposure to Dantrolene. 5. It is argued that the reduction of Ca2+ efflux by Dantrolene does not result from any direct inhibitory effect on the metabolically driven Ca pump at the outer membrane, but that it is rather related to the reduction of the concentration of myoplasmic Ca2+ which is indeed demonstrated by the reduced resting glow. This in turn is thought to result from a shift in the balance between Ca2+ movements into and out of the intracellular storage sites, and namely the sarcoplasmic reticulum (SR). 6. The Ca2+ transient in aequorin-loaded fibres and the force of the isometric contraction elicited by imposed membrane depolarizations were markedly reduced by Dantrolene. The electrochemical threshold for eliciting intracellular Ca2+ release was not significantly modified. The linear relation between membrane depolarization and Ca2+ transient became less steep. The process of sequestration of myoplasmic Ca2+ back into SR was not significantly affected by Dantrolene which appeared to inhibit rather selectively the Ca2+ release from SR into the cytosol.

Animals↗

PubMed1977

Dantrolene sodium: a review of its pharmacological properties and therapeutic efficacy in spasticity.

Dantrolene sodium or dantrolene1 is 1([5-(nitrophenyl)furfurylidend] amino) hydantoin sodium hydrate. It is indicated for use in chronic disorders characterised by skeletal muscle spasticity, such as spinal cord injury, stroke, cerebral palsy and multiple sclerosis. Dantrolene is believed to act directly on the contractile mechanism of skeletal muscle to decrease the force of contraction in the absence of any demonstrated effects on neural pathways, on the neuromuscular junction, or on the excitable properties of the muscle fibre membranes. Controlled trials have demonstrated that dantrolene is superior to placebo in adults or children with spasticity from various causes, as evidenced by clinical assessments of disability and daily activities, and by muscle and reflex responses to mechanical and electrical stimulation. It is somewhat less effective in patients with multiple sclerosis than in those with spasticity from other causes. There has been a general clinical impression in controlled trials that dantrolene caused less sedation than would have been expected from therapeutically comparable doses of diazepam. In 2 controlled trials, there was no significant difference between dantrolene and diazepam in terms of reductions in spasticity, clonus, and hyperreflexia, but side-effects such as drowsiness and inco-ordination occurred significantly more frequently on diazepam. Long-term studies have indicated continuing benefit for patients taking dantrolene, though the incidence of side-effects has often been high and there has been a suggestion of exacerbation of seizures in children with cerebral palsy. Dantrolene may be of value in the medical treatment of spasm of the external urethral sphincter due to neurological and non-neurological disease, and animal studies suggest a potential use in the management of malignant hyperpyrexia. Chemical evidence of liver dysfunction may occur in 0.7 to 1% of patients on long-term treatment with dantrolene, with symptomatic hepatitis in 0.35 to 0.5% and fatal hepatitis in 0.1 to 0.2%. The drug commonly causes transient drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea at the start of therapy. Muscle weakness may be the principal limiting side-effect in ambulant patients, particularly in those with multiple sclerosis, and therapy could be hazardous in patients with pre-existing bulbar or respiratory weakness. The dosage of dantrolene has been fixed in most controlled trials, though long-term studies have indicated the need for individualisation of dosage. The initial dose is usually 25mg once daily, increasing to 25mg two, three or four times daily, and then by increments of 25mg up to as high as 100mg two, three or four times daily. The lowest dose compatible with optimal response is recommended.

Adult↗

PubMed1977

Inhibitory action of dantrolene sodium on the activation of excitation-contraction coupling in frog skeletal muscle.

Effect of dantrolene sodium on the activation of potassium contracture in single fibers of frog semitendinosus muscle was studied. Dantrolene shifted the activation curve to the right without changing the depolarization produced by a given K+ concentration. The shift of mechanical threshold by dantrolene was dependent on the concentration of calcium in the medium and the effects of dantrolene and Ca++ are additive to each other. On the other hand, the action of dantrolene is antagonized by Ca++ with respect to the peak tension in 190 mM K+. In addition, dantrolene did not release 45Ca from the self-exchangeable Ca fraction and did not affect the exchange of 45Ca in the self-exchangeable Ca fraction with 40Ca. It was also observed that dantrolene had no appreciable influence on the ultrastructure of muscle fibers under our experimental conditions. On the basis of these results, the mechanism of action of dantrolene on the activation of excitation-contraction coupling, the relation between the drug and calcium actions and the drug effect on the Ca movement in T-system membranes were discussed.

Animals↗

PubMed1977

The mechanism of action of dantrolene sodium.

Dantrolene sodium is thought to affect some step in the excitation-contraction coupling process. Using a point voltage clamp to determine mechanical thresholds of individual fibers of frog, rat and goat skeletal muscle preparations, we found that dantrolene both raises (moves to more positive potentials) the rheobasic potential and increases the steepness of the strength-duration curve for mechanical threshold. The effect of raising the rheobase reaches a maximum at 1.2 x 10-5M dantrolene whereas the steepness effect occurs only at a saturating concentration (3.8x10-5M),indicating that dantrolene has two sites of action. The rheobase effect is absent below 18 degrees C (suggesting a phase transition) and it is competitively antagnoized by the calcium ionophore A23187 which can release calcium from the sarcoplasmic reticulum. The data indicate that dantrolene raises the rheobase by directly decreasing the release of calcium from the sarcoplasmic reticulum. We propose that dantrolene inhibits the movement of a natural calcium ionophore. Measurements of the voltage-dependent charge movement associated with excitation-contraction coupling showed that dantrolene did not significantly change the amount of charge moved. The time to peak of the ON current was not significantly changed, but that of the OFF current was significantly shortened. This action of dantrolene on the kinetics of the OFF current may account for its effect on the steepness of the strength-duration curve.

Animals↗

PubMed1978

Dantrolene blocks intracellular calcium release in smooth muscle: competitive antagonism of thromboxane A2.

Dantrolene sodium has been shown to block the release of intracellular calcium in skeletal muscle. It has been proposed that dantrolene blocks the movement and (or) action of a natural calcium ionophore. In a rat vascular preparation dantrolene was found to inhibit pressor responses to noradrenaline and angiotensin but not those to potassium with an IC50 concentration within the therapeutic levels in man. Imidazole, an inhibitor of thromboxane A2 (TXA2) synthesis, had similar actions to dantrolene. Interactions between imidazole and dantrolene suggested that dantrolene may be a competitive antagonist of TXA2 in muscle. We report the first demonstration of an effect of dantrolene sodium on smooth muscle contractility and suggest that TXA2 is an essential modulator of vascular reactivity. A similar role has been shown for TXA2 in platelets.

Angiotensin II↗

PubMed1978

Dantrolene sodium: effects on smooth muscle.

The effects of dantrolene sodium on smooth muscle were evaluated in vitro using the guinea pig ileum and the guinea pig vas deferens preparations. Dantrolene irreversibly decreased the strength of the responses of the ileum to acetylcholine, histamine, potassium chloride and electrical stimulation. Doubling the concentration of calcium in the bathing media reduced the effect of dantrolene on all agonists. Dantrolene irreversibly decreased the response of the vas deferens to epinephrine, norepinephrine, acetylcholine and electrical stimulation. Doubling the concentration of calcium in the bathing media reduced the effect of dantrolene on all agonists. Dantrolene seems to depress smooth muscle as it does skeletal muscle. The mechanism of action probably involves the reduction of calcium flux into the muscles.

Animals↗

PubMed1975

Effect of dantrolene sodium on excitation-contraction coupling in frog skeletal muscle.

The effect of dantrolene sodium, 1-(5-(p-nitrophenyl)furfuryli-deneamino)hydantoin sodium hydrate, on electrical and mechanical response in frog skeltal muscles (whole muscles or single fibers) and on the biochemical properties of contractile proteins and fragmented sarcoplasmic reticulum isolated from frog or rabbit skeletal muscle was investigated. The peak tensions of twitch, tetanus and potassium contracture were significantly inhibited by dantrolene, without affecting the magnitude of resting potential, the amplitude and duration of action potential and the negative afterpotential. On the other hand, ATP-INDUCED SHORTENING OF GLYCEROL-EXTRACTED RABBIT PSOAS MUSCLE FIBERS, ATPase activity of frog myofibrils and Ca release induced by caffeine, Ca uptake and ATPase activity of fragmented sarcoplasmic reticulum of frog or rabbit muscle were not affected by dantrolene. Caffeine contracture was partially inhibited by dantrolene and was almost unchanged by it in potassium-depolarized muscele fiber. Nitrate ions and low concentration of caffeine rapidly recovered the twitch inhibition induced by dantrolene. These results suggested that dantrolene acts on the membrane of transverse tubules and possibly the triadic junction and that it inhibits the inward movement of Ca and subsequently decreases the release of activator Ca from sarcoplasmic reticulum.

Action Potentials↗

PubMed1979

Relationship between plasma concentration and effect of dantrolene sodium in man.

Dantrolen sodium is a muscle relaxant, which is used in the treatment of spasticity. Although it is given chronically, little is known about its pharmacokinetic behaviour. The relationship between the effect of a single oral dose of dantrolene sodium and its plasma concentration in healthy volunteers was studied by measuring the effect on the twitch tension, and in spastic patients on the decrease in muscle hypertonia. On the twitch tension dantrolene gave a depression of 49.1 +/- 9.4% (+/- DS) within 1.15 and 3.45 h after ingestion of 100 mg. The mean maximal plasma concentration was 1.24 +/- 0.32 microgram/ml (+/- SD). The effect and the plasma concentration were correlated. No relationship between the plasma concentration of dantrolene sodium and its effect could be established in patients, although definite activity in 6 out of 7 patients was observed after a single oral dose of 100 mg, and plasma concentration of dantrolene sodium greater than 0.3 microgram/ml were consistenly associated with better results than placebo treatment in 6 out of 7 patients.

Adult↗

PubMed1976

The effects of dantrolene sodium on cardiac and skeletal muscle in rats.

Dantrolene sodium in different concentrations was administered to the spontaneously beating heart placed in a modified Langendorff apparatus. Heart frequency and contractility were recorded. Dantrolene sodium was also administered to the rat diaphragm. Twitch tension after indirect supramaximal stimulation was recorded. Dantrolene sodium produced a long lasting dose-dependent reduction of the contractility of the isolated rat heart up to 75% of control values. It had no effect on the heart frequency. The drug also decreased the force of contraction of the rat skeletal muscle in vitro to the same extent. The diaphragm appeared to be more sensitive to low concentrations of dantrolene sodium than was heart muscle i.e. the dose-response curve on rat diaphragm was flatter. It may be concluded however that higher concentrations of dantrolene sodium may effect the contractility of heart muscle as well and that this may have clinical implications.

Animals↗

PubMed1979

Rationale for dantrolene vs. procainamide for treatment of malignant hyperthermia.

The use of procainamide or procaine for treatment of malignant hyperthermia is commonly recommended. The skeletal muscle relaxant dantrolene has also been indicated for treatment of this complication during anesthesia. In the present study, effects of procainamide and dantrolene were compared in malignant hyperthemia-susceptible (MHS) pigs in vivo and on MHS muscle from human patients in vitro. The ED50 for dantrolene block of indirectly evoked twitch tension was 0.85 mg/kg in MHS pigs. A final cumulative dose of 2 mg/kg resulted in 68 per cent block of the twitch response. In contrast, procainamide at a final cumulative dose of 14 mg/kg had no effect on twitch response of the MHS pigs. Dantrolene, 3 micrometer, in vitro (approximately 0.8 mg/kg in vivo) was effective in preventing or reversing the abnormal halothane-induced contracture response of human MHS muscle strips. Procainamide, 0.11 mM, a dose approximating clinical levels (about 22 mg/kg), had no effect on basal twitch response or on the abnormal halothan-induced contracture of MHS human muscle. These results confirm the effectiveness of dantrolene and the lack of effectiveness of procainamide in the treatment of malignant hyperthemia.

Animals↗

PubMed1978

The effect of dantrolene sodium on the efflux of Ca45 from rat heavy sarcoplasmic reticulum.

The effect of dantrolene on calcium (Ca2+) efflux was studied using SR vesicles isolated at 8,000 X G from rat skeletal muscle. Dantrolene concentrations of 4 to 9 X 10(-5) M suppressed the efflux of Ca45 from the isolated vesicles in a dose-related way during the first 5 minutes of incubation. The residual Ca2+ in the sarcotubular vesicles was inversely related to the dantrolene concentrations of 4, 6 and 9 X 10(-5) M. The addition of 10mM caffeine to the efflux media offset the suppressive effects of the lower concentrations of dantrolene on Ca2+ efflux. Only dantrolene concentrations of 9 X 10(-5)M resulted in significant retention of Ca2+ in the vesicles in the presence of 10mM caffeine.

Animals↗

PubMed1977

Some antagonists of dantrolene sodium on the isolated diaphragm muscle of the rat.

The effects of a number of potential antagonists of dantrolene sodium have been studied on twitches of the isolated hemidiaphragm preparation of the rat stimulated directly at a frequency of 0-1 Hz, after complete neuromuscular block produced by tubocurarine or erabutoxin a. The substances selected as possible dantrolene antagonists were uranyl ions, thiocyanate ions, adrenaline, caffeine, quazodine, quinine, 4-aminopyridine and the calcium ionophore a23187, all of which facilitate excitation-contraction coupling in one way or another. Contracture was the main feature of the response to A23187, the increase in the tension of the dantrolene-depressed twitches being very slight. All the remaining compounds increased the amplitude of the twitches, but only 4-aminopyridine, quinine, quazodine and caffeine were capable of restoring to the control amplitude twitches that had been maximally depressed by dantrolene. OF these, 4-aminopyridine and quinine were the most potent on a molar basis.

Animals↗

PubMed1979

Effect of dantrolene sodium on the incidence of seizures in children with spasticity.

In this two-phase study, 21 pediatric patients with epilepsy and spasticity were initially treated with dantrolene sodium suspension and, after a washout period, began a double-blind portion where one half received dantrolene sodium suspension and the other half received a placebo suspension. The frequency of seizures, serum anticonvulsant levels and electroencephalograms were compared with control values. On dantrolene sodium suspension, there was no persistent change in these parameters. Therefore, it is concluded that dantrolene sodium does not adversely affect the frequency of seizures in children with epilepsy and spasticity, who are being maintained on anticonvulsant medications.

Adolescent↗

PubMed1977

[Effects of dantrolene sodium on some types of visceral muscles (author's transl)].

Twitch contraction height of the outer layer of esophagus was reduced by 5 X 10(-6) g/ml of dantrolene to 7% of the height observed before the application. High-K induced contracture of this preparation and of cremaster muscle were also depressed to 14% and to 18% of the control, respectively. When dantrolene (25 X 10(-6) g/ml) was applied during the contracture induced by 9.7 X 10(-4) g/ml of caffeine, a complete relaxation was observed. Dantrolene had no effect either on the evoked twitch contraction of the smooth muscle of vas deferens or on spontaneous contractions of the taenia coli. High-K induced contracture of these smooth muscles was not affected by dantrolene. Electron micrograph showed that the outer layer of esophagus and cremaster muscle were composed of striated muscle cells in which the sarcoplasmic reticulum, transverse tubulus, and triadic junctions were well developed. In smooth muscle preparations, although sarcoplasmic reticula were observed, neither transverse tubula nor triadic junctions comparable to those in the striated muscle were evident. These morphological differences may explain differences in the action of the drug.

Animals↗

PubMed1979

Pleuropericardial reaction to treatment with dantrolene.

Chronic pleural effusion occurred in three patients, one of whom also developed acute pericarditis. A fourth patient developed both pleural and pericardial effusions. All patients had been receiving dantrolene sodium for at least two months. The pleural fluid was a sterile exudate with pleural and peripheral blood eosinophilia in all patients. No pulmonary parenchymal involvement was apparent. Pleural biopsy specimens showed nonspecific inflammation. Resolution of the pleural process was prolonged after dantrolene therapy was discontinued. Although a causal relationship between dantrolene and serosal inflammation remains unproved, this association in four patients warrants careful observation of others receiving long-term dantrolene therapy.

Acute Disease↗

PubMed1978

Reversible effect of dantrolene sodium on twitch tension of rat skeletal muscle.

The effect of dantrolene sodium on twitch tension in skeletal muscle of the rat was studied in short- and long-term experiments. The twitch tension is reduced to 50% of the control values within 20 to 30 minutes of drug administration. The recovery phase is considerably slower than the effect observed on the addition of dantrolene sodium, having a half time of 10 hours. Twenty-four hours after the drug injection, the twitch tension in the treated muscles is indistinguishable from that in the controls. It is shown that the reduction in the magnitude of the twitch produced by dantrolene sodium is slowly and completely reversible.

Animals↗