M.A. Denborough

INHERITANCE OF MALIGNANT HYPERPYREXIA

Abstract Serum-creatine-phosphokinase (C.P.K.) levels, clinical examination, and retrospective information on 18 propositi and their families have identified at least three groups of individuals who are susceptible to malignant hyperpyrexia. All 6 survivors tested had high serum-C.P.K. levels, and the results of this study suggest that all individuals who develop malignant hyperpyrexia have one of a number of specific susceptible myopathies. The first susceptible group of patients have a dominantly inherited myopathy. This was found in 9 of the 18 families, but in 6 of these the myopathy was not clinically detectable in affected individuals. In 3 of the 9 families an overt myopathy was present, and in the most severely affected of these a characteristic clinical picture was found. All 9 families may have had the same myopathy, with considerable heterogeneity of clinical expression. Three propositi from normal families were probably mutants for the dominant myopathy (or myopathies). The second group of susceptible individuals consists of some patients who have myotonia congenita, another example of which was found in this series. The third group consists of patients with physical abnormalities and a progressive congenital myopathy. This was found in five young males with short stature, cryptorchidism, pectus carinatum, lumbar lordosis, and thoracic kyphosis. Three had a similar facies.

Sources of calcium for contraction of guinea-pig isolated tracheal smooth muscle.

1. Contractile responses of guinea‐pig tracheal smooth muscle to KC1, histamine, acetylcholine and prostaglandins were reduced after the removal of extracellular Ca2+ from the bathing medium.

MYOPATHY AND MALIGNANT HYPERPYREXIA

Abstract A patient, who had survived malignant hyperpyrexia, and three of his close relatives were found to have very high levels of serum-creatine-phosphokinase (C.P.K.). Although the patients muscles seemed normal two of the three relatives had a mild but definite myopathy, affecting predominantly the lower muscles of the thigh. It seems that malignant hyperpyrexia develops in individuals with a myopathy which is inherited as an autosomal dominant, and which may be subclinical.

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.

MALIGNANT HYPERPYREXIA AND SUDDEN INFANT DEATH

The muscle-membrane disorder which predisposes to malignant hyperpyrexia, a complication of anaesthesia, has been identified in 5 of 15 parents whose children had died from sudden infant death syndrome. This observation raises the possibility that an acute disorder of myoplasmic calcium metabolism may be implicated in some sudden infant deaths.

Anaphylaxis in guinea-pig peripheral airways in vitro

The contributions made by histamine, prostaglandins (PG) and slow reacting substance (SRS-A) to anaphylactic contractions in isolated guinea-pig lung were investigated. Histamine, PGF2alpha and SRS-A induced isometric contractions in lung parenchymal strips and in tracheal smooth muscle. The effective concentrations of the autacoids were the same in lung strips and tracheas. Anaphylactic contractions in lung strips from bovine serum albumin sensitised animals were not affected by mepyramine (5 X 10(-6)M), or indomethacin (3 X 10(-5)M) but were markedly reduced by FPL 55712 (5 X 10(-5)M) suggesting that SRS-A plays a major role in the anaphylactic response. The effect of isoprenaline on anaphylactic histamine release and contractions was also examined. Anaphylactic contractions in lung strips were inhibited by isoprenaline (10(-10)--10(-7)M). Isoprenaline also inhibited anaphylactic histamine release from lung parenchyma. 10(-7)M isoprenaline inhibited contractions by 85.6% and reduced histamine release by 27.9%. The results suggest that histamine release does not contribute markedly to anaphylaxis in peripheral airways.

The pathopharmacology of malignant hyperpyrexia

Abstract Malignant hyperpyrexia is a dangerous complication of anaesthesia which occurs in individuals who have an underlying disease of muscle. Two predisposing myopathies have been defined. Studies in susceptible humans and in swine, with an apparently identical myopathy, have shown that when MH muscle is exposed to a precipitating anaesthetic agent there is a sudden rise in the concentration of calcium ions in the myoplasm. The precise nature of the inherited muscle membrane abnormality is not yet known, but pharmacological and biochemical studies indicate that is closely associated with the excitation-contraction coupling mechanism.

Procaine in malignant hyperpyrexia.

The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture. The muscle from a patient with an inherited susceptibility to malignant hyperpyrexia contracted spontaneously with halothane alone, and this contracture was reversed by procaine. These experiments support the therapeutic use of procaine in malignant hyperpyrexia.

A study of the action of caffeine, halothane, potassium chloride and procaine on normal human skeletal muscle.

SUMMARY 1. The effects of caffeine, halothane, potassium chloride and procaine have been studied on normal human skeletal muscle in vitro. Particular emphasis has been given to the role played by extracellular calcium ions in producing these effects.

STUDIES ON NORMAL HUMAN SKELETAL MUSCLE IN RELATION TO THE PATHOPHARMACOLOGY OF MALIGNANT HYPERPYREXIA

1. The effects of dantrolene on pharmacologically‐induced contractures and potentiated isometric twitches in normal human skeletal muscle have been studied in vitro.