Dantrolene, a Direct Acting Skeletal Muscle Relaxant

Ellis, K. O.; Castellion, Alan W.; Honkomp, Leroy J.; Wessels, F. L.; Carpenter, John F.; Halliday, Robert P.

doi:10.1002/jps.2600620619

Cited by 76 publications

(24 citation statements)

References 5 publications

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“…These stastics and further data are illustrated in Figure 5, which shows that dantrolene sodium causes a loss of tetanic tension, the actual amplitude of which is dependent both on the applied stimulation frequency and the type of motor unit to which it is applied. Thus (Ellis et al, 1973;Nott & Bowman, 1974;Ellis et al, 1976;Bowman et al, 1979;Mai & Pedersen, 1979;Leslie & Part, 1981a). However, as mentioned in the Introduction, there are limitations to the whole muscle approach.…”

Section: (Ii) Hind Limb Musclesmentioning

confidence: 99%

The action of dantrolene sodium on individual fast and slow motor units of the rat anaesthetized with urethane

Leslie

Part

1984

British J Pharmacology

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Section: (Ii) Hind Limb Musclesmentioning

confidence: 99%

The action of dantrolene sodium on individual fast and slow motor units of the rat anaesthetized with urethane

Leslie

Part

1984

British J Pharmacology

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“…1 MH is a potentially deadly, pharmacogenetically mediated, hypermetabolic response to volatile anesthetics that results from unregulated intramyoplasmic Ca 2ϩ release (1). The drug is known to inhibit excitation-contraction coupling of skeletal muscle (2) by suppressing depolarization-induced sarcoplasmic reticulum (SR) Ca 2ϩ release in normal and MH-susceptible skeletal muscle without affecting voltage sensor activation (3). In MH, the voltage dependence of contractile activation is shifted to lower voltages (4), whereas in the presence of clinical concentrations of dantrolene, i.e.…”

mentioning

confidence: 99%

Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

Kobayashi

Bannister

Gangopadhyay

et al. 2005

Journal of Biological Chemistry

120

111

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Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca 2؉ channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The SternVolmer quenching constant (K Q ) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22°C and was unaffected by calmodulin. [ 3 H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca 2؉ release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37°C, yet required the presence of calmodulin at 22°C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca 2؉ channel opening rather than the domain switch itself.Dantrolene (hydrated 1-(((5-(4-nitrophenyl)-2-furanyl)methylene)amino)-2,4-imidazolidinedione sodium salt) is an intracellularly acting skeletal muscle relaxant used for the treatment of malignant hyperthermia (MH). 1 MH is a potentially deadly, pharmacogenetically mediated, hypermetabolic response to volatile anesthetics that results from unregulated intramyoplasmic Ca 2ϩ release (1). The drug is known to inhibit excitation-contraction coupling of skeletal muscle (2) by suppressing depolarization-induced sarcoplasmic reticulum (SR) Ca 2ϩ release in normal and MH-susceptible skeletal muscle without affecting voltage sensor activation (3). In MH, the voltage dependence of contractile activation is shifted to lower voltages (4), whereas in the presence of clinical concentrations of dantrolene, i.e. 10 M (5), the voltage dependence of contractile activation is shifted to higher voltages (6, 7). Normalization of the voltage dependence of contractile activation may therefore be one of the important components of the therapeutic action of dantrolene. Dantrolene also confers a normal Mg 2ϩ sensitivity to MH-susceptible muscle fibers, which would otherwise show a considerably reduced sensitivity to the normal inhibitory action of myoplasmic Mg 2ϩ on the SR Ca 2ϩ release mechanism (...

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“…The first studies to specifically address the effects of dantrolene on cardiovascular function evaluated healthy anesthetized dogs and showed no relevant effects on arterial pressure, central venous pressure, heart rate, coronary blood flow and cardiac output [77][78] . Later, other authors argumented that those results did not imply absence of effects on cardiovascular functions, since mechanisms of compensation may have had a role in maintaining the stability of the parameters investigated 79 .…”

Section: Side Effectsmentioning

confidence: 99%