Malignant hyperthermia.

A specific inherited muscle membrane disorder predisposes to a variety of clinical problems. The most common is malignant hyperthermia (MH), a dangerous hypermetabolic state after anaesthesia with suxamethonium and/or volatile halogenated anaesthetic agents. MH may also be triggered in susceptible individuals by severe exercise in hot conditions, infections, neuroleptic drugs, and overheating in infants.

Overheating alone can trigger malignant hyperthermia in piglets.

Seven out of eight piglets which were susceptible to malignant hyperthermia (MHS) died when subjected to a heat challenge which was well tolerated by controls. The piglets which succumbed developed the classical clinical and biochemical changes of malignant hyperthermia before they died. These results show that overheating alone can trigger malignant hyperthermia in susceptible animals.

Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia.

The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in a small proportion of cases. We report here that one of these, the Arg163Cys substitution, does not cosegregate with MH susceptibility. Comparison of cDNA sequences encoding the skeletal muscle specific components of the dihydropyridine receptor alpha 1 subunit between MH susceptible (MHS) and MH non-susceptible (MHN) patients was made in subjects without the reported MH linked RYR1 mutations.

Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.

We have cloned and sequenced the cDNA encoding triadin, a junctional terminal cisternae protein from human skeletal muscle. The cDNA, 2941 base pairs in length, encodes a protein of 729 amino acids with a predicted molecular mass of 81,545 Da. Hydropathy analysis indicates that triadin of human skeletal muscle has the same topology in the myoplasmic, transmembrane and sarcoplasmic reticulum luminal domains as that of triadin from rabbit skeletal muscle.

The metabolism of D-myo-inositol 1,4,5-trisphosphate and D-myo-inositol 1,3,4,5-tetrakisphosphate by porcine skeletal muscle.

In soluble and particulate extracts from muscle D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] are metabolised stepwise to inositol. Ins(1,4,5)P3 is rapidly dephosphorylated to D-myo-inositol 1,4-bisphosphate then to D-myo-inositol 4-phosphate and finally inositol. In soluble extracts Ins(1,3,4,5)P4 is dephosphorylated to D-myo-inositol 1,3,4-trisphosphate then sequentially to D-myo-inositol 3,4-bisphosphate, D-myo-inositol 3-phosphate and inositol, while in particulate extracts D-myo-inositol 1,3-bisphosphate is the predominant inositol bisphosphate formed.

Purification and characterization of D-myo-inositol (1,4,5)/(1,3,4,5)- polyphosphate 5-phosphatase from skeletal muscle.

In this investigation we report the presence of two forms of inositol (1,4,5)P3/(1,3,4,5)P4-polyphosphate 5-phosphatase activity (types I and II) which were observed in soluble extracts of skeletal muscle after fractionation by DEAE-Sephacel chromatography. Hydrolysis of D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and D-myo-inositol 1,3,4,5-tetrakisphosphate by both phosphatases was 5-phosphate-specific, Mg2+ ion-dependent and inhibited by D-2,3-bisphosphoglycerate. Soluble type I 5-phosphatase activity was purified 27,300-fold to a specific activity of 2.

Kinetic analysis of novel inhibitors of inositol polyphosphate metabolism.

The ability of the novel D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3] analogues, L-chiro-inositol 1,4,6-trisphosphate [L-chr Ins(1,4,6)P3] and the corresponding trisphosphorothioate compound [L-chr Ins(1,4,6)PS3] to inhibit soluble inositol (1,4,5)P3/(1,3,4,5)P4-polyphosphate 5-phosphatase, potently and selectively, has been investigated. L-chr Ins(1,4,6)P3 competitively inhibited 5-phosphate specific dephosphorylation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] with apparent Ki values of 6.35 and 1.

A clinical grading scale to predict malignant hyperthermia susceptibility.

Background: The diagnosis of an acute malignant hyperthermia reaction by clinical criteria can be difficult because of the nonspecific nature and variable incidence of many of the clinical signs and laboratory findings. Development of a standardized means for estimating the qualitative likelihood of malignant hyperthermia in a given patient without the use of specialized diagnostic testing would be useful for patient management and would promote research into improved means for diagnosing this disease.

Methods: Using the Delphi method and an international panel of 11 experts on malignant hyperthermia, a multifactor malignant hyperthermia clinical grading scale comprising standardized clinical diagnostic criteria was developed for classification of existing records and for application to new patients.

Detection and partial purification of inositol 1,4,5-trisphosphate 3-kinase from porcine skeletal muscle.

A myoplasmic 3-kinase was detected in porcine skeletal muscle that phosphorylated [3H]Ins(1,4,5)P3 [D-myo-inositol(1,4,5)trisphosphate] to [3H]Ins(1,3,4,5)P4 [D-myo-inositol(1,3,4,5)tetrakisphosphate]. The Ins(1,4,5)P3 3-kinase activity was ATP- and Mg(2+)-dependent, and was activated by Ca2+ and calmodulin. Ins(1,4,5)P3 3-kinase activity was purified 2632-fold from soluble extracts of skeletal muscle by a combination of DEAE-Sephacel, heparin-Agarose and Ins(1,4,5)P3 structural-analogue affinity chromatography.

The effect of calcium channel antagonists and BAY K 8644 on calcium fluxes of malignant hyperpyrexia-susceptible muscle.

1. The calcium channel antagonists verapamil (100 microM) and nifedipine (100 microM) inhibited twitch response and KCl induced hypercontractility in malignant hyperpyrexia (MH)-susceptible porcine skeletal muscle. These calcium channel antagonists did not effect hypercontractility induced by 3% halothane or 2 mM caffeine.

Propofol anaesthesia in malignant hyperpyrexia susceptible swine.

1. Malignant hyperpyrexia (MH) is an inherited muscle abnormality that presents clinically as a syndrome of life-threatening complications during general anaesthesia. 2.

The effect of azumolene on hypercontractility and sarcoplasmic reticulum Ca(2+)-dependent ATPase activity of malignant hyperpyrexia-susceptible porcine skeletal muscle.

1. Azumolene sodium is a new water-soluble derivative of dantrolene sodium that also acts as a skeletal-muscle relaxant. 2.

Effect of diltiazem, verapamil and dantrolene on the contractility of isolated malignant hyperpyrexia-susceptible human skeletal muscle.

1. Diltiazem (10 mumol/L) and verapamil (10 mumol/L) inhibited the hypercontractility induced by 3% halothane and 2 mmol/L caffeine in malignant hyperpyrexia susceptible (MHS) muscle. Diltiazem also inhibited 80 mmol/L KCl contractures.

Inositol 1,4,5-trisphosphate phosphatase deficiency and malignant hyperpyrexia in swine.

The sarcoplasmic reticulum from muscle of swine which are susceptible to malignant hyperpyrexia is deficient in inositol 1,4,5-trisphosphate phosphatase (InsP35-ase) activity, which leads to high intracellular concentrations of inositol 1,4,5-trisphosphate (InsP3) and of calcium ions. Halothane inhibits InsP35-ase and further increases myoplasmic InsP3 and calcium ion concentrations, and produces the clinical features of malignant hyperpyrexia.

Effect of diltiazem and dantrolene on the contractility of isolated malignant hyperpyrexia-susceptible porcine skeletal muscle.

Diltiazem inhibited and antagonized the abnormal contractures induced by halothane, caffeine and potassium chloride in isolated skeletal muscle from pigs susceptible to malignant hyperpyrexia (MHS). Contractile responses to caffeine and electrical stimulation also were suppressed by diltiazem in control tissue. Similar effects were obtained in the presence of dantrolene.

Effect of diltiazem on porcine malignant hyperpyrexia induced by suxamethonium and halothane.

We have studied the ability of the calcium channel antagonist diltiazem to inhibit and reverse the porcine malignant hyperpyrexia (MH) syndrome. Pretreatment with diltiazem modified an MH response. Treatment with diltiazem was partially effective against a mild (or early) MH response.