Dantrolene -In vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle

Britt, Beverley A.; Scott, Elizabeth; Frodis, Wanda; Clements, Mary-Jean; Endrényi, László

doi:10.1007/bf03015252

Cited by 26 publications

(9 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on its ability to inhibit release of Ca2+ from the sarcoplasmic reticulum and thereby suppress contraction of skeletal muscles (Ellis et al, 1976), Dantrolene is clinically used in the therapy of malignant hyperthermia (Britt et al, 1984) and spasticity (Pinder et al, 1977). Due to the muscle activity, KA-induced seizures are accompanied by an increase in body temperature, and this increase is inhibited by Dantrolene.…”

Section: Discussionmentioning

confidence: 99%

Kainic acid‐induced seizures and brain damage in the rat: Role of calcium homeostasis

Berg

Bruhn

Frandsen

et al. 1995

J of Neuroscience Research

View full text Add to dashboard Cite

Seizure activity induced by kainic acid (KA) and subsequent neuronal death are thought to be associated with an increase in cytoplasmic free calcium ([Ca2+]i) and can be prevented by N-methyl-D-aspartate (NMDA) antagonists. In addition to influx through receptor operated Ca2+ channels the increase in [Ca2+]i may be the result of an increased influx through voltage-operated calcium channels and/or release from intracellular deposits. It was therefore investigated whether compounds other than NMDA antagonists with known actions on the intracellular Ca2+ homeostasis had any protective effect against KA-induced neuronal death. Voltage-operated calcium channels in the cell membrane were blocked with the L-type ion channel antagonist, Nimodipine (1.0 mg/kg), and release of Ca2+ from internal stores was prevented with Dantrolene (10 mg/kg). Animals from two control groups injected with kainate (8 mg/kg) exhibited a survival rate of 67 and 53%, respectively. Countings of neurons in dorsal hippocampus showed subtotal or total loss in the CA1 and CA3 subregions. There were no significant differences concerning seizure and survival rates in the groups injected with kainate and treated with Dantrolene or Nimodipine and the control groups. The group treated with Dantrolene showed no neuropathological changes in the hippocampal CA3 region and only slight changes in the Ca1 region, while the neuron loss in the Nimodipine group did not differ from that of its control group. The results emphasize the importance of Dantrolene-sensitive Ca2+ release from intracellular stores for the development of seizure-induced neuronal death.

show abstract

Section: Discussionmentioning

confidence: 99%

Kainic acid‐induced seizures and brain damage in the rat: Role of calcium homeostasis

Berg

Bruhn

Frandsen

et al. 1995

J of Neuroscience Research

View full text Add to dashboard Cite

show abstract

“…Dantrolene (1-5 M) has been reported to have a biphasic effect on the open probability of RyR1 channels in lipid bilayers, first activating and then blocking at nanomolar concentrations (16), but others have not been able to see any effect of this drug on single channels (3). Importantly, dantrolene has been shown to at least partially restore the normal properties of RyR1 Ca 2ϩ channels in SR isolated from MH-susceptible pigs (1,17,18). Thus, these studies together suggest that dantrolene interacts with the RyR to suppress the channel dysfunction that occurs with MH mutations.…”

mentioning

confidence: 99%

Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

Kobayashi

Bannister

Gangopadhyay

et al. 2005

Journal of Biological Chemistry

120

111

View full text Add to dashboard Cite

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 (...

show abstract

“…Thus, the uncontrolled SR Ca 2ϩ release, muscle contracture, and accelerated metabolism that threaten the MH-susceptible (MHS) patient exposed to volatile anesthetics during surgery are effectively suppressed upon treatment with dantrolene (9,10). Dantrolene also reverses the increased sensitivity of MHS muscle to activation by caffeine (11), which constitutes the basis of in vitro diagnostic tests of this syndrome (12,13). The efficacy of dantrolene in the treatment of MH is in large part a function of the selective action of this drug on SR Ca 2ϩ release in skeletal muscle, while exerting no comparable negative inotropic effect on the beating heart (6,10,14).…”

mentioning

confidence: 99%

Dantrolene Inhibition of Ryanodine Receptor Ca2+Release Channels

Zhao

Пин

Chen

et al. 2001

Journal of Biological Chemistry

298

215

View full text Add to dashboard Cite

As an inhibitor of Ca 2؉ release through ryanodine receptor (RYR) channels, the skeletal muscle relaxant dantrolene has proven to be both a valuable experimental probe of intracellular Ca 2؉ signaling and a lifesaving treatment for the pharmacogenetic disorder malignant hyperthermia. However, the molecular basis and specificity of the actions of dantrolene on RYR channels have remained in question. Here we utilize 2؉ . In contrast to the RYR1 isoform, the cardiac RYR2 isoform was unaffected by dantrolene, both in native cardiac SR vesicles and when heterologously expressed in HEK-293 cells. By comparison, the RYR3 isoform expressed in HEK-293 cells was significantly inhibited by dantrolene, and the extent of RYR3 inhibition was similar to that displayed by the RYR1 in native SR vesicles. Our results thus indicate that both the RYR1 and the RYR3, but not the RYR2, may be targets for dantrolene inhibition in vivo.

show abstract

Dantrolene -In vitro studies in malignant hyperthermia susceptible (MHS) and normal skeletal muscle

Abstract: and EKG monitoring of all patients during anaesthesia is, therefore, essential.

Cited by 26 publications

References 51 publications

Kainic acid‐induced seizures and brain damage in the rat: Role of calcium homeostasis

Kainic acid‐induced seizures and brain damage in the rat: Role of calcium homeostasis

Dantrolene Stabilizes Domain Interactions within the Ryanodine Receptor

Dantrolene Inhibition of Ryanodine Receptor Ca2+Release Channels

Contact Info

Product

Resources

About