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Biomedical subjects

M A Denborough

Publications and source records attributed to M A Denborough.

At least 19 recordsLinked to original sources
PubMed1992

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.

Anesthesia↗
PubMed1991

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.

Animals↗
PubMed1989

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.

Animals↗
PubMed1989

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.

Animals↗
PubMed1989

31P-NMR spectroscopy: the metabolic profile of malignant hyperpyrexic porcine skeletal muscle.

31Phosphorus-NMR spectroscopy may have the potential to help in the noninvasive diagnosis of malignant hyperpyrexia (MH). Changes in the phosphate-metabolite profile of MH-susceptible (MHS) skeletal muscle occur more readily under conditions of anoxia than in control muscle. Induction of anoxia caused a rapid fall in intracellular phosphocreatine, an elevation of inorganic phosphate, and finally a diminution of ATP in MHS muscle. The onset of metabolic change was slower in control tissue. Increased oxygen consumption may occur in anoxic MHS muscle, which leads to accelerated glycolysis and a rapid fall in the intracellular high-energy phosphates. In MHS muscle an abnormality may exist in carbohydrate metabolism linked with poor resynthesis of the high-energy phosphates, which may be precipitated under anaerobic conditions. Accelerated muscle metabolism is also observed in the presence of 2 mM caffeine and 3% halothane in MHS muscle. Changes in the concentrations of metabolites could be mapped noninvasively under anoxic conditions using topical 31P-NMR.

Animals↗
PubMed1989

Characterization of the terminal cisternae and longitudinal tubules of sarcoplasmic reticulum from malignant hyperpyrexia susceptible porcine skeletal muscle.

1. The sarcoplasmic reticulum (SR) from malignant hyperpyrexia susceptible (MHS) and control porcine skeletal muscle was separated into vesicular fractions enriched in the membrane elements of the terminal cisternae and longitudinal tubules. 2. The two membrane preparations were highly purified and had distinctive features which were associated with their origins in the SR membraneous network. 3. Calsequestrin and calcium were enriched in the terminal cisternae fraction (HSR), in comparison to longitudinal tubule preparations (LSR). 4. The HSR membrane also had a greater total capacity to store Ca2+ and Ca2+ release was more rapid than from LSR preparations. 5. No distinction could be made between the membrane morphology, Ca2+ -fluxes or Ca2+ -dependent ATPase activities, associated with these functionally distinct regions of MHS and control preparations.

Animals↗
PubMed1989

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.

Anesthesia↗
PubMed1989

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. In both MHS and control preparations, diltiazem antagonized caffeine-induced contractures in the presence of maximal effective concentrations of dantrolene, and the converse was true also. In MHS and control preparations detubulated by glycerol, diltiazem did not inhibit or antagonize caffeine-induced contractures while dantrolene did. Diltiazem seems to modify contractile responses at the level of the transverse tubule membrane by inhibiting the inward flow of extracellular Ca2+, while dantrolene inhibits Ca2+ release directly from the sarcoplasmic reticulum. Ca2+ influx through transverse tubules may be important in the aetiology of the MH syndrome.

Animals↗
PubMed1989

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.

Caffeine↗
PubMed1988

Calmodulin-antagonist drugs and porcine malignant hyperpyrexia.

1. Landrace swine were identified as malignant hyperpyrexia susceptible (MHS) or control by the contracture responses of gracilis muscle fibre bundles to 3% halothane, 2 mmol/l caffeine and 80 mmol/l KCl. The effects of calmodulin-antagonist drugs on the contractile behaviour of control and MHS preparations were investigated in vitro. 2. Calmodulin-antagonists at micromolar concentrations induced contracture in both control and MHS muscle. Pretreatment of MHS muscle with calmodulin-antagonist drugs potentiated its response to halothane and caffeine. 3. These results suggest that calmodulin-antagonist drugs cause an increase in myoplasmic Ca2+ concentration in both control and MHS muscle.

Animals↗
PubMed1987

Thiophosphorylation of skeletal muscle sarcoplasmic reticulum in porcine malignant hyperpyrexia.

1. The basal, Ca2+-dependent and Mg2+-dependent thiophosphorylation of malignant hyperpyrexia-susceptible (MHS) porcine skeletal muscle was investigated. 2. Seven major proteins of Mr 100,000-11,000 were substrates for thiophosphorylation. 3. Sodium molybdate significantly elevated all levels of thiophosphorylation in control sarcoplasmic reticulum, but did not effect the Ca2+-dependent thiophosphorylation of MHS samples. 4. These results suggest that MHS sarcoplasmic reticulum may have altered sensitivity to protein phosphatase inhibition.

Adenosine Triphosphate↗
PubMed1987

Calmodulin in porcine malignant hyperpyrexia.

The anaesthetic complication malignant hyperpyrexia (MH) is due to an elevation of the myoplasmic Ca2+ concentration. Examination of calmodulin isolated from MH susceptible swine suggests that the disorder in calcium regulation in MH is not due to an abnormality in calmodulin.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

The effects of calmodulin antagonist drugs on isolated sarcoplasmic reticulum from malignant hyperpyrexia susceptible swine.

1. Because calcium antagonist drugs increase contracture in both control and malignant hyperpyrexia susceptible (MHS) skeletal muscle, the effect of these drugs on the sarcoplasmic reticulum (SR) was investigated. 2. The calmodulin antagonist drugs inhibited the Ca2+ dependent ATPase activity and the ATP-dependent Ca2+ uptake, and accelerated the efflux of Ca2+ from isolated SR preparations from both control and MHS skeletal muscle. These effects of calmodulin antagonist drugs on SR Ca2+ transport functions were consistent with their in vitro pharmacological effects on control and MHS muscle.

Adenosine Triphosphate↗
PubMed1987

Effects of adenylate cyclase activators on porcine skeletal muscle in malignant hyperpyrexia.

The effect of adenylate cyclase activation on the in vitro contractures of control and malignant hyperpyrexia susceptible (MHS) porcine muscle was investigated. While fluoride and molybdate ions potentiated drug-induced contractures in control muscle, other activators of adenylate cyclase (forskolin and noradrenaline) did not. Furthermore, fluoride and molybdate had no effect on MHS skeletal muscle contractility. Cyclic AMP content, basal adenylate cyclase activity and molybdate-stimulated adenylate cyclase activity of MHS skeletal muscle was not significantly different from that of control muscle. It is concluded that increased activity of adenylate cyclase does not represent the primary skeletal muscle defect which predisposes to porcine MH.

Adenylyl Cyclases↗
PubMed1987

The effect of oxytocin on porcine malignant hyperpyrexia susceptible skeletal muscle.

1. Certain commercial preparations of oxytocin have been reported to reverse the development of pale soft exudative meat and malignant hyperpyrexia (MH) in pigs in vitro. 2. In this study it is shown that preservative-free oxytocin has no significant effect on the characteristic contractures of MH susceptible (MHS) muscle to halothane, caffeine, succinylcholine and KCl in vitro. 3. Whilst a commercial preparation of oxytocin, Syntocinon (containing chlorbutol as preservative), reversed and prevented the MHS characteristic responses, this study demonstrates conclusively that this was entirely due to the preservative chlorbutol.

Animals↗
PubMed1986

Suxamethonium chloride and malignant hyperpyrexia.

Pure suxamethonium chloride does not produce in vitro contracture of skeletal muscle from swine which are susceptible to malignant hyperpyrexia (MH), but does induce MH in vivo. It is suggested that suxamethonium chloride induces MH because the fasciculations which it causes lead to an increase in the myoplasmic calcium concentration.

Animals↗