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. Because the biochemical basis of malignant hyperthermia is similar in both humans and pigs, these observations suggest that overheating can also trigger malignant hyperthermia in humans. The susceptibility to overheating in malignant hyperthermia susceptible humans and animals probably explains why the myopathy which predisposes to this condition has also been reported to predispose to heat-stroke and the sudden infant death syndrome. In view of this, particular care to prevent overheating should be taken in infants of parents who are susceptible to malignant hyperthermia.

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. Propofol is a new sedative hypnotic used for the induction and maintenance of anaesthesia. 3. Propofol did not induce MH in five susceptible pigs. Propofol did not induce contracture in isolated MH susceptible muscle but did modify halothane, caffeine and KCl contractures.

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. Azumolene (6 mumol/L) inhibited the hypercontractility induced separately by 3% halothane, 2 mmol/L caffeine and 80 mmol/L potassium chloride in isolated malignant hyperpyrexia (MH)-susceptible muscle. Azumolene was equipotent with dantrolene in inhibiting the abnormal responses. 3. Like dantrolene, azumolene (6 mumol/L) not only prevented but reversed the abnormal contractures induced by halothane and caffeine. Contracture responses to caffeine were also modified by azumolene in control preparations. 4. In the presence of maximal effective concentrations of dantrolene, azumolene failed to further relax caffeine-induced contractures, and the converse was also true. This was observed in both MH-susceptible and control preparations. 5. Sarcoplasmic reticulum Ca(2+)-dependent ATPase activity from MH-susceptible and control muscle was not affected by azumolene. 6. Like dantrolene, azumolene may inhibit Ca2+ release directly from the sarcoplasmic reticulum and be of therapeutic value for the treatment of MH.

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. 2. Like the skeletal muscle relaxant dantrolene sodium (6 mumol/L), diltiazem not only prevented but reversed the abnormal contractures induced by halothane and caffeine. 3. The effect on caffeine contractures of diltiazem and dantrolene in combination was additive. 4. The ability of diltiazem and verapamil to inhibit the hypercontractility of MHS muscle suggests that Ca2+ influx across the transverse tubular membrane may be important in the aetiology of the malignant hyperpyrexia syndrome. 5. These results also suggest an abnormality in transverse tubule-sarcoplasmic reticulum communication.

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 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. Diltiazem should not be considered to be an effective therapeutic agent for MH and should not displace the use of dantrolene.

Calcium currents and asymmetric charge movement in malignant hyperpyrexia.

In both control pigs and pigs susceptible to malignant hyperpyrexia (MH), the size of the calcium current (ICa) and the amount of asymmetric charge movement varied considerably between different gracilis muscle fibers but appeared to vary in parallel. The mean amount of both ICa and charge movement were slightly but significantly smaller in MH-susceptible (MHS) muscle compared with normal muscle. Halothane (1% v/v) reduced both parameters by almost 50%. One interpretation of the data is that the signal, which couples depolarization to calcium release from the sarcoplasmic reticulum, is abnormal in MHS muscle.