HALF-UFE OF PLASMA CHOLINESTERASE

The half-life of plasma choJinesterase (acylcholine acylhydrolase,EC3.1.1.8) was determined by measurement of the rate of reappearanceof enzyme activity after marked depletion associated with repeatedplasma nrrhangn in two patients. Half-life values of S.O and5.4 days were found     

EFFECT OF NEOSTIGMINE AND PYRIDOSTIGMINE ON THE PLASMA CHOLINESTERASE ACTIVITY

The effect of neostigmine 0.05mg kg^–1 or pyridostigmine0.25mg kg^–1 on serum cholinesterase activity was investigatedin 20 adult patients undergoing elective surgery. Both drugsproduced marked depression of enzymatic activity. The maximaldepression was observed in samples taken 5mm after injection.The maximal percentage depression of enzymatic activity wasnot significantly different in the two drug groups. However,at 30–60mm after injection, the degree of depression wasless in the neostigmine group. This may be attributed to thedifferent plasma clearances of neostigmine and pyridostigmine.     

PLASMAPHERESIS AND PLASMA CHOLINESTERASE

Plasma cholinesterase (E.C. 3.1.1.8 [EC] ) concentrations were measuredin nine outpatients who were undergoing regular plasmapheresis.A single plasmapheresis produced a 64% reduction in cholinesteraseconcentration compared with the value before plasmapheresis.Another patient who received four plasma exchanges in 6 daysshowed a progressive reduction in cholinesterase concentrationto only 8% of the initial value. It is suggested that drugsmetabolized by cholinesterase should be used with caution inpatients undergoing plasmapheresis, particularly when frequentpalsma exchanges are undertaken. ^*Present address: Department of Anaesthetics, Northwick ParkHospital, Watford Road, Harrow, Middlesex HA1 3UJ.     

DETERMINATION OF THE SERUM CHOLINESTERASE

Some of the variables which influence the results of determinationof serum cholinesterase are reviewed. These include substrateconcentration, pH and temperature. There is also a considerablevariation between different workers in methods of expressionof results.     

THE EFFECT OF PROPRANOLOL ON AIRWAY RESISTANCE

The effect of propranolol on the airway resistance (AWR) ofeighteen normal and seven asthmatic subjects has been studiedby whole body plethysmography. In normal subjects there wasa significant mean rise in AWR which was never accompanied byany respiratory upset. In asthmatic subjects there was a greatermean rise in AWR which usually resulted in dyspnoea and occasionallywheezing. In nine subjects, the studies were repeated afterthe prior administration of atropine which almost completelyabolished the rise in AWR after propranolol in normal subjectsand markedly reduced the rise in asthmatic subjects. The modeof action of propranolol in producing bronchoconstriction isdiscussed and the protective effect of atropine is stressed. ^* Present address: Department of Anaesthesia, University ofGlasgow, Western Infirmary, Glasgow, W.2.     

INHIBITION OF MITOCHONDRIAL RESPIRATION BY SODIUM NITROPRUSSIDE AND THE MECHANISM OF CYANIDE LIBERATION

The influence of sodium nitroprusside (SNP) on mitochondrialrespiration was examined in rat liver mitochondria. The additionof SNP 1 mmol litre^-1 during state 3 respiration inhibited theoxygen uptake by 63.4%. A mixture of SNP 1 mmol litre^-1 andglutathione (GSH) 1 mmol litre^-1 inhibited the oxygen uptakemore markedly (by 75.9%). The cyanide concentrations were 0.01mmol litre^-1 with SNP alone and 0.15 mmol litre^-1 with the mixtureof SNP and GSH. Cyanide production from SNP in the presencevarious reducing agents was studied in potassium phosphate 0.1mol litre^-1 buffer solution (pH 7.4) incubated at 37°. Cyanidewas liberated markedly from SNP in the presence of GSH or ascorbate.Less cyanide was produced in the presence of NADH of NADPH.The rate production of cyanide was dependent entirely upon theconcentration of each reducing agent added. No cyanide was liberatedwhen sodium dithionite or the oxidezed forms of GSH, NAD orNADP were used. It was concluded that SNP is degradated to cyanideby a hydrogen donor and that the cyanide liberated in this mannerinhibits the cytochrome oxidase activity of mitochondria invivo     

EFFECT OF PROPRANOLOL ON THE VENTRICULAR ARRHYTHMIAS INDUCED BY HYPERCARBIA DURING HALOTHANE ANAESTHESIA IN MAN

The effects of propranolol on arterial blood pressure, heartrate, and cardiac rhythm during ventricular arrhythmias initiatedby hypercarbia were investigated in thirteen subjects during1 per cent halothane anaesthesia. Propranolol was consistentlyeffective in the treatment of ventricular arrhythmia inducedby hypercarbia in all subjects. The successful use of propranololsuggests that the mechanism for ventricular arrhythmia producedby respiratory acidosis during halothane anaesthesia was relatedto beta adrenergic receptors. Blockade of these receptors bybeta adrenergic agents decreased markedly the sensitizationof myocardium to sympathetic stimulation.     

THE EFFECT OF TEMPERATURE ON FLUORIDE-RESISTANT SERUM CHOLINESTERASE

Two individuals homozygous for the fluoride-resistant serumcholinesterase have been found in two generations of one family.A study of the variation with temperature of serum cholincsteraseactivity and the effect of inhibitors confirms earlier theoreticalpredictions     

THE INFLUENCE OF THE KALLIKREIN-TRYPSIN INACTIVATOR TRASYLOL ON THE SERUM CHOLINESTERASE

In a study of 28 patients suffering from a wide variety of diseases,the kallikrein-trypsin inactivator Trasylol (FBA) was foundto have an inhibitory action on the serum cholinesterase 30minutes after the administration of the drug. The average fallin serum cholinesterase at this time was 25.4 per cent. Valueshad returned to normal levels at 60 minutes.     

ANALGESIC EFFECT OF APROTININ IN THE RAT AND ITS INHIBITION BY NALOXONE

Experiments were performed on rats using two analgesimetrictests (tail-flick; hot-plate) before and after injection i.v.of graded doses of apruunin (12.5, 25.0 and 50 KIU g^–1).A dose-related analgesic effect was noted with both tests. Prioradministration of naloxone 0.001 mg g^–1 i.p. inhibitedthe analgesic action.     

EFFECT OF PROPRANOLOL ON ARTERIAL HYPOTENSION INDUCED BY HALOTHANE IN THE DOG UNDER NITROUS OXIDE ANAESTHESIA

The effect of propranolol hydrochloride on arterial hypotensionproduced by halothane has been investigated in atropinized dogsduring nitrous oxide-oxygen anaesthesia. Propranolol alone produceda slight transient fall in blood pressure, but greatly enhancedthe hypotensive action of halothane. Following the applicationof electric shock to the heart to terminate adrenaline-inducedventricular fibrillation during halothane-nitrous oxide anaesthesia,propranolol produced a profound fall in arterial pressure. Ashock-like state associated with marked bradycardia resulted.Therapy with adrenaline and mephentermine produced slow recovery,and the pressor response was not associated with any increasein heart rate. The outcome of pressor therapy was related tothe number of electric shocks applied to the heart. Two dogsin which electric shock was applied thrice failed to recoverin spite of vigorous pressor therapy. It is suggested that cautionshould be exercised when injecting propranolol during halothaneanaesthesia in humans. The use of this drug following the applicationof electric shock to the heart to terminate ventricular fibrillationmay be hazardous and should be avoided.     

INHIBITION OF WOUND CONTRACTION BY TOPICAL ANTIMICROBIALS

Spontaneous wound healing occurs partly by wound contraction, a process that requires intact functioning fibroblasts, and collagen production. Disruption of fibroblasts by the topical antimicrobials, silver sulfadiazine and mafenide acetate has been demonstrated in vitro. An acute rat wound model was used to show that wound contraction in vivo is significantly impeded by silver sulfadiazine and mafenide acetate.     

EFFECTS OF PROPRANOLOL ON THE ACTION OF NEUROMUSCULAR BLOCKING DRUGS

The neuromuscular block induced in cats by depolarizing drugswas intensified and the effect of tubocurarine was reduced byintravenous infusions of propranolol, although by themselvesthey did not affect contraction of skeletal muscle.     

INHIBITION OF FETAL METHIONINE SYNTHASE BY NITROUS OXIDE

The activity of the enzyme methionine synthase in fetal andmaternal liver was investigated before and after exposure tonitrous oxide. Timed-pregnant rats on day 19 of gestation wereexposed to either 10% or 50% nitrous oxide for various timesup to 240 min. After exposure, fetal and maternal livers wereremoved and methionine synthase activity assayed. Normal methioninesynthase activity in the fetus was about 50% of that in themother. Both fetal and maternal methionine synthase activitydecreased progressively with increasing time of exposure tonitrous oxide and recovered only slowly after the agent wasdiscontinued.     

SERUM CHOLINESTERASE: EFFECT ON THE ACTION OF SUXAMETHONIUM FOLLOWING ADMINISTRATION TO A PATIENT WITH CHOLINESTERASE DEFICIENCY

Purified serum cholinesterase 90 mg was administered to a patientwith cholinesterase deficiency. The effect on the action ofsuxamethonium was studied. The half-life (44.7 h), time constant(64.5 h), rate constant (0.0155 h^–1) and distributionvolume (2740 ml) of the cholinesterase activity were determined.     

INHIBITION OF NEURONAL AND EXTRANEURONAL UPTAKE OF NORADRENALINE BY KETAMINE IN THE ISOLATED PERFUSED RAT HEART

The effect of ketamine on the uptake of 3H-noradrenaline inthe isolated perfused rat heart was studied. A dose-dependentinhibition of uptake by both neuronal and extraneuronal processeswas found. These effects may account for the positive chronotropicand pressor effects of the drug.     

IN VITRO INTERACTION OF PROPANIDID AND SUXAMETHONIUM WITH POOLED HUMAN PLASMA CHOLINESTERASE: A Kinetic Study

Human plasma cholinesterase (E.C. 3.1.1.8 [EC] ) was shown to be inhibitedby physiological concentrations of propanidid and suxamethoniumusing a colourimetric assay at 25 °C and pH 7.2 unit withbutyrylthiocholine as substrate. Propanidid inhibited the enzymein a non-competitive manner (/50 = 2.0 mmol litre1; apparentKm 6.6 x 10–4 mollitre"1) as did suxamethonium (/60 =4.4 mmol litre1; apparent Km 1.6 x 10–4 mol litre1). Combinedinhibition produced Km 3.0 x 10–3 mol litre"1. The bindingof these drugs to specific anionic sites in the vicinity ofthe active centre is thought to result in stereochemical changesin the enzyme. This mechanism and its relevance to the augmentationof the neuromuscular blockade produced by suxamethonium in thepresence of propanidid is discussed.     

COLLABORATIVE STUDY OF THE FREQUENCY OF THE FLUORIDE-RESISTANT CHOLINESTERASE VARIANT IN PATIENTS WITH MALIGNANT HYPERPYREXIA

Cholinesterase phenotyping studies have been carried out intwo laboratories on blood specimens from 28 patients shown tobe susceptible to malignant hyperpyrexia. In contrast to previouslypublished reports, no evidence could be found for an increasein the frequency of the E₁^uE₁^f genotype above that known tooccur in the general population.     

A SOURCE OF ERROR IN THE DETERMINATION OF INHIBITOR CONSTANTS OF SERUM CHOLINESTERASE

The effect of temperature on the inhibition of serum cholinesteraseby dibucaine, fluoride and chloride has been studied. It isfound that the dibucaine and chloride numbers together are capableof differentiating the inherited enzyme variants at 30°and 37° C. Fluoride numbers contribute little informationat these temperatures; indeed fluoride inhibition is so sensitiveto temperature change that unless rigid temperature controlis maintained in current techniques, erroneous conclusions maybe drawn. A family with unusual chloride numbers is revealed.