THE ACTION OF DANTROLENE SODIUM ON RAT FAST AND SLOW MUSCLE <i>in vivo</i>

Leslie, G. C.; Part, N. J.

doi:10.1111/j.1476-5381.1981.tb09147.x

Cited by 38 publications

(44 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In each preparation care was taken to stabilize the proximal tendon of the muscle whilst the distal tendon, now cut from its insertion, was attached to the force transducer (Devices 2ST 05, 0-100 g). Thereafter the bath was filled with pre-warmed liquid paraffin maintained at 35 to 37°C by warm water circulating through a second chamber in the base of the bath (see Andrew & Part, 1972; Leslie & Part, 1981a (Andrew & Part, 1972).…”

Section: Methodsmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…That was accomplished by using dantrolene sodium, a specific inhibitor of sarcoplasmic reticulum Ca 2+ release (14)(15)(16). The purpose of this study was to investigate if staircase potentiation could be restored in atrophied muscle after dantrolene treatment without concomitant increases in R-LC phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Staircase in mammalian muscle without light chain phosphorylation

Rassier

Tubman

MacIntosh

1999

Braz J Med Biol Res

View full text Add to dashboard Cite

In disuse atrophied skeletal muscle, the staircase response is virtually absent and light chain phosphorylation does not occur. The purpose of the present study was to determine if staircase could be restored in atrophied muscle with continued absence of myosin light chain phosphorylation, by reducing what appears to be an otherwise enhanced calcium release. Control (untreated) and sham-operated female Sprague-Dawley rats were compared with animals after 2 weeks of complete inactivity induced by tetrodotoxin (TTX) application to the left sciatic nerve. In situ isometric contractile responses of rat gastrocnemius muscle were analyzed before and after administration of dantrolene sodium (DS), a drug which is known to inhibit Ca 2+ release in skeletal muscle. Twitch active force (AF) was attenuated by DS from 2.2 ± 0.2 N, 2.7 ± 0.1 N and 2.4 ± 0.2 N to 0.77 ± 0.2 N, 1.05 ± 0.1 N and 1.01 ± 0.2 N in TTX (N = 5), sham (N = 11) and control (N = 7) muscles, respectively. Following dantrolene treatment, 10 s of 10-Hz stimulation increased AF to 1.32 ± 0.2 N, 1.52 ± 0.1 N and 1.45 ± 0.2 N for the TTX, sham and control groups, respectively, demonstrating a positive staircase response. Regulatory light chain (R-LC) phosphorylation was lower for TTX-treated (5.5 ± 5.5%) than for control (26.1 ± 5.3%) and sham (20.0 ± 5%) groups. There was no significant change from resting levels for any of the groups after DS treatment (P = 0.88). This study shows that treatment with dantrolene permits staircase in atrophied muscle as well as control muscle, by a mechanism which appears to be independent of R-LC phosphorylation.

show abstract

“…Functional studies on muscle fibers suggested the RyR as the potential target for the action of dantrolene (25,26), and respective binding sites were mapped to the protein (27)(28)(29). However, no action of dantrolene was found in most studies on single RyRs incorporated into lipid bilayers (26,30,31).…”

mentioning

confidence: 99%

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Choi

Koenig

Launikonis

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca 2+ transients elicited by MH triggers are unknown. Here, we show that Ca 2+ release in the absence of Mg 2+ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg 2+ ] (free [Mg 2+ ] cyto ) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca 2+ waves in the presence of resting levels of free [Mg 2+ ] cyto (1 mM). However, an increase of free [Mg 2+ ] cyto to 1.5 mM could increase the period between Ca 2+ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg 2+ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg 2+ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg 2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode. malignant hyperthermia | dantrolene | ryanodine receptor | magnesium | skeletal muscle fiber R yanodine receptors (RyRs) are essential regulators of cytoplasmic Ca 2+ in muscle, heart, and brain (1-3). Congenital or acquired mishandling of Ca 2+ by RyRs is associated with organ dysfunction, myopathy, and the increased risk of sudden death (1, 4-7). Consequently, the search for drugs to modulate RyR function is an area of intense research (8-10). An example of a successful drug controlling the Ca 2+ mishandling of the RyR is the muscle relaxant dantrolene (11). It is primarily used to treat malignant hyperthermia (MH), a life-threatening condition in which genetically predisposed individuals adversely react to the exposure of volatile anesthetics (5, 12). Since its approval, the drug has cut the mortality rate associated with MH from more than 80% to below 2% (11). Despite this success, the exact mechanism of how dantrolene antagonizes MH episodes and depresses overactive Ca 2+ release during MH episodes remains unknown.Susceptibility to MH most commonly arises from mutations in the RyR1 gene, the Ca 2+ release channel of skeletal muscle. Mg 2+ is present in the muscle at ∼1 mM and exerts an inhibitory action over the RyR1, which needs to be overcome for normal voltagecontrolled Ca 2+ release (13-16). RyR1 variants have a lowered affinity for Mg 2+ (13,17), making them more prone to opening and resulting in increased sensitivity to RyR agonist. The ensuing abnormal Ca 2+ release in RyR variants (18-24) during an MH event leads to excessive heat production as the muscle attempts to clear the...

show abstract

THE ACTION OF DANTROLENE SODIUM ON RAT FAST AND SLOW MUSCLE in vivo

Cited by 38 publications

References 15 publications

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

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

Staircase in mammalian muscle without light chain phosphorylation

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia

Contact Info

Product

Resources

About

THE ACTION OF DANTROLENE SODIUM ON RAT FAST AND SLOW MUSCLE in vivo

Cited by 38 publications

References 15 publications

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

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

Staircase in mammalian muscle without light chain phosphorylation

Dantrolene requires Mg 2+ to arrest malignant hyperthermia

Contact Info

Product

Resources

About

Dantrolene requires Mg ²⁺ to arrest malignant hyperthermia