The Effect of Azumolene on Hypercontractility and Sarcoplasmic Reticulum Ca2+‐dependent Atpase Activity of Malignant Hyperpyrexiasusceptible Porcine Skeletal Muscle

Foster, Paul S.; Hopkinson, K.C.; Payne, N E; Denborough, M. A.

doi:10.1111/j.1440-1681.1991.tb01482.x

Cited by 10 publications

(5 citation statements)

References 17 publications

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“…In vivo , azumolene was even more potent than dantrolene in inhibiting gastrocnemius muscle twitches [65]. The excitability and contractility of cardiac muscle were not affected by either dantrolene or azumolene when given in therapeutic doses [65, 66].…”

Section: New Developmentsmentioning

confidence: 99%

Dantrolene – A review of its pharmacology, therapeutic use and new developments

et al. 2004

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SummaryHuman malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.

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Section: New Developmentsmentioning

confidence: 99%

Dantrolene – A review of its pharmacology, therapeutic use and new developments

et al. 2004

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“…Finally, the role of calcium in sepsis-induced release of myofilaments was assessed by treating rats with dantrolene, which is a substance that blocks the release of calcium from intracellular stores (21). Rats were injected s.c. on the back with 10 mg/kg dantrolene or corresponding volume of solvent (7.5% mannitol/NaOH solution, pH 9.0) 2 h before and 8 h after sham operation or CLP, and release of myofilaments was determined in EDL muscles 16 h after CLP or sham operation.…”

Section: Experimental Animalsmentioning

confidence: 99%

Sepsis stimulates release of myofilaments in skeletal muscle by a calcium‐dependent mechanism

et al. 1999

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Sepsis is associated with a pronounced catabolic response in skeletal muscle, mainly reflecting degradation of the myofibrillar proteins actin and myosin. Recent studies suggest that sepsis-induced muscle proteolysis may reflect ubiquitin-proteasome-dependent protein breakdown. An apparently conflicting observation is that the ubiquitin-proteasome pathway does not degrade intact myofibrils. Thus, it is possible that actin and myosin need to be released from the myofibrils before they can be ubiquitinated and degraded by the proteasome. We tested the hypothesis that sepsis results in disruption of Z-bands, increased expression of calpains, and calcium-dependent release of myofilaments in skeletal muscle. Sepsis induced in rats by cecal ligation and puncture resulted in increased gene expression of micro-calpain, m-calpain, and p94 and in Z-band disintegration in the extensor digitorum longus muscle. The release of myofilaments from myofibrillar proteins was increased in septic muscle. This response to sepsis was blocked by treating the rats with dantrolene, a substance that inhibits the release of calcium from intracellular stores to the cytoplasm. The present results provide evidence that sepsis is associated with Z-band disintegration and a calcium-dependent release of myofilaments in skeletal muscle. Release of myofilaments may be an initial and perhaps rate-limiting component of sepsis-induced muscle breakdown.

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“…The caffeine-halothane contracture (CHC) test was carried out with the same techniques and criteria used in previous studies (e.g., Foster et al, 1991;Owen et al, 1997). Each muscle bundle (2.5 cm long and 3 mm in diameter) was suspended vertically under 1.5 g of resting tension in an organ bath chamber containing the above-mentioned saline solution at 37°C, and the force was recorded when the bundle was challenged with either halothane (ICI, Australia; administered with carbogen at 3% v/v through a Dragewick vaporizer) or with a range of caffeine concentrations (2 mM, 4 mM, and 8 mM) produced by cumulative addition to the bathing medium.…”

Section: Caffeine-halothane Contracture Testmentioning

confidence: 99%

Reduced inhibitory effect of Mg2+ on ryanodine receptor-Ca2+ release channels in malignant hyperthermia

Laver¹,

Owen²,

Junankar³

et al. 1997

Biophysical Journal

112

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Malignant hyperthermia (MH) is a potentially fatal, inherited skeletal muscle disorder in humans and pigs that is caused by abnormal regulation of Ca2+ release from the sarcoplasmic reticulum (SR). MH in pigs is associated with a single mutation (Arg615Cys) in the SR ryanodine receptor (RyR) Ca2+ release channel. The way in which this mutation leads to excessive Ca2+ release is not known and is examined here. Single RyR channels from normal and MH-susceptible (MHS) pigs were examined in artificial lipid bilayers. High cytoplasmic (cis) concentrations of either Ca2+ or Mg2+ (>100 microM) inhibited channel opening less in MHS RyRs than in normal RyRs. This difference was more prominent at lower ionic strength (100 mM versus 250 mM). In 100 mM cis Cs+, half-maximum inhibition of activity occurred at approximately 100 microM Mg2+ in normal RyRs and at approximately 300 microM Mg2+ in MHS RyRs, with an average Hill coefficient of approximately 2 in both cases. The level of Mg2+ inhibition was not appreciably different in the presence of either 1 or 50 microM activating Ca2+, showing that it was not substantially influenced by competition between Mg2+ and Ca2+ for the Ca2+ activation site. Even though the absolute inhibitory levels varied widely between channels and conditions, the inhibitory effects of Ca2+ and Mg2+ were virtually identical for the same conditions in any given channel, indicating that the two cations act at the same low-affinity inhibitory site. It seems likely that at the cytoplasmic [Mg2+] in vivo (approximately 1 mM), this Ca2+/Mg2+-inhibitory site will be close to fully saturated with Mg2+ in normal RyRs, but less fully saturated in MHS RyRs. Therefore MHS RyRs should be more sensitive to any activating stimulus, which would readily account for the development of an MH episode.

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The Effect of Azumolene on Hypercontractility and Sarcoplasmic Reticulum Ca2+‐dependent Atpase Activity of Malignant Hyperpyrexiasusceptible Porcine Skeletal Muscle

Cited by 10 publications

References 17 publications

Dantrolene – A review of its pharmacology, therapeutic use and new developments

Dantrolene – A review of its pharmacology, therapeutic use and new developments

Sepsis stimulates release of myofilaments in skeletal muscle by a calcium‐dependent mechanism

Reduced inhibitory effect of Mg2+ on ryanodine receptor-Ca2+ release channels in malignant hyperthermia

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