barium-induced in the rat, totraction the effects of barium chloride on muscle contraction elicited...

Journal of Neurology, Neurosurgery, and Psychiatry, 1974, 37, 32-39

Barium-induced skeletal muscle paralysis in the rat,and its relationship to human familial periodic

paralysisG. D. SCHOTT AND B. McARDLE1

From the Department of Chemical Pathology, Guy's Hospital, London

SUMMARY An in vivo study of skeletal muscle paralysis induced by intravenous barium chloride hasbeen made in curarized and non-curarized rats. The influence of potassium and calcium chlorides,propranolol, ouabain, and prior adrenalectomy on the paralysis has also been studied. Paralysis isfound to be due to a direct effect on skeletal muscle, and to correlate well with the development ofhypokalaemia. Possible mechanisms of action of barium are discussed, and attention is drawn to thesimilarity between barium poisoning and hypokalaemic familial periodic paralysis.

The similarity between periodic paralysis andbarium poisoning was first appreciated in China.An endemic illness, Pa Ping, characterized bysometimes fatal episodes of paralysis, was formany years prevalent in the Szechwan provinceof western China.A series of papers on Pa Ping, introduced by

that of Allen (1943), reported in considerabledetail the investigation of the disease, and itscause was traced to the very high barium contentin the local salt. Huang (1943) wrote that thecases ' showed symptoms almost completelyidentical with the description of the rare diseasecalled "family periodic paralysis" . . .', and sug-gested that a disturbance in 'the potassium ionequilibrium in the body' might be responsible.Only very occasional reference to this strikingobservation has since been made (Diengott et al.,1964; Zierler, 1970), and despite its similarity toperiodic paralysis, few investigations have beendescribed of the way in which the soluble salts ofthis element exert their profound and character-istic effect. Hypokalaemia associated withbarium poisoning was demonstrated, togetherwith the electrocardiographic (ECG) changestypical of low plasma potassium, by Diengott etal. (1964).

Paralysis of skeletal muscle, flaccid in type, is afrequent though not invariable feature of barium1 Member of the External Scientific Staff, Medical Research Council.

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poisoning. The weakness, which occasionally ispreceded by a diffuse aching in the muscles,affects earliest and most severely the limbs, butmay proceed to involvement of the trunk, andlater the respiratory, neck, and bulbar muscula-ture. It is global in distribution, and unrelated tonerve distribution. There are no apparent charac-teristic features indicative of its aetiology.The present experiments have been undertaken

to investigate some aspects of this paralysis, andin particular to ascertain the site of the paralysingaction of barium. Although barium has severalother effects on man and animals (Welt andBlythe, 1970), these effects-which includehypertension, smooth muscle stimulation, andproduction of cardiac arrhythmias-have notbeen specifically investigated during the courseof this study.

METHODS

Experiments were performed on Wistar strain GH2rats of either sex, weighing 150-250 g, anaesthetizedwith intraperitoneal urethane (15 ml./kg of a 100solution). Respiration where necessary was main-tained with a ventilator pump (Palmer). Contrac-tions of the gastrocnemius/plantaris/soleus musclegroup were elicited indirectly by stimulation of thedistal end of the cut sciatic nerve, using rectangularcurrent pulses of 0-5 msec duration delivered at arate of 6/min, and about twice the strength necessary

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Barium-induced skeletal muscle paralysis in the rat

to produce a maximal twitch. Directly-elicited con-tractions of the fully curarized tibialis anteriormuscle were obtained by similar means, using a silverwire attached to the musculotendinous junction anda steel needle electrode driven into the femur.

Pilot experiments indicated that complete andmaintained neuromuscular blockade was producedby intravenous injections of tubocurarine, 0-6 mg/kg,repeated at 20 to 30 minute intervals, and curariza-tion thus effected avoided the necessity for two simul-taneous infusions (see below).

Muscles were bathed continuously in mineral oil(heavy liquid paraffin B.P.) maintained at a tempera-ture of 37+ 10 C, recorded in the fluid a few milli-metres away from the muscle. The rectal temperaturewas also kept at 370 C by means of a heating lampplaced above the animal. The leg was firmly clampedas horizontally as possible to reduce heat loss(Bigland and Zaimis, 1958), the resting length of themuscle adjusted to give a maximum twitch tension,and contractions recorded on a 4-channel recorder(Devices), by means of an isometric tension trans-ducer (E.E.L., Model 2ST02) attached to theappropriate tendon.Drugs were injected intravenously through a

cannula in the jugular vein, or intra-arteriallythrough a cannula introduced into the femoralartery of the leg contralateral to that subsequently tobe dissected. Arterial blood samples were also ob-tained from this cannula. Carotid blood pressure wasrecorded continuously using a pressure transducer(Consolidated Electrodynamics, Model 4-327-L221),and heart-rate by means of an instantaneous rate-meter (Devices). Adrenalectomy where indicated wasperformed through bilateral paravertebral incisions,immediately after induction of anaesthesia. Despitethe similar results obtained with barium chloridemade up in isotonic saline, and the negligiblequantity of chloride introduced, barium chloride wasmade up in isotonic sodium acetate, since certainelectrophysiological experiments (Sperelakis et al.,1967) had indicated that chloride could have a mask-ing action on some barium-induced effects. Thebarium chloride solution was administered by slowintravenous infusion, using a motorized syringe(Palmer); and in experiments in which plasma bariumconcentration was determined, 131BaC12 (Radio-chemical Centre, Amersham) was added, to provideapproximately 20 ,uc/ml. barium chloride solutioninjected. The radioactive barium contributed less than0-1% total barium injected; and the arterial plasmabarium concentration was determined by measure-ment of radioactivity, using a well scintillationcounter (Dynatron). Arterial plasma sodium andpotassium concentrations were determined by flamephotometry (Instrumentation Laboratories, Model

143), preliminary experiments demonstrating theabsence of effect of barium on this technique. Plasmafor these determinations was obtained by one minutecentrifugation in a Beckman Spinco-152 microfugeof 0-2 ml. blood samples, the latter being replacedwith the same volume of 0-900 w/v saline.The drugs used were: d-tubocurarine chloride

(Burroughs Wellcome); barium chloride, 2H20;calcium chloride, 2H20; potassium chloride (BritishDrug Houses); isoprenaline sulphate B.P. (Mac-arthy); propranolol hydrochloride (Imperial Chemi-cal Industries), ouabain (Nativelle Laboratories).Aqueous stock solutions were used, diluted with0.90o w/v saline where appropriate, except in thecase of barium chloride solution. The drugs wereadministered in a volume of 0-1-0 5 ml., and flushedin with 0-2 ml. 0-900 w/v saline. Solutions areexpressed in terms of the salts.

RESULTS

EFFECTS OF BARIUM CHLORIDE ON MUSCLE CON-

TRACTION The effects of barium chloride onmuscle contraction elicited by supramaximal in-direct and direct muscle stimulation are illus-trated respectively in Figs 1 and 2. Both show thesame features, found to be consistent in thoseanimals in which unequivocal paralysis was ob-tained by use of an effective dose of bariumchloride (see below), and in which the animal'sgeneral condition remained unimpaired, as indi-cated by maintenance of a satisfactory bloodpressure, and where appropriate, respiration.These effects consist of: (1) a period of increasedmuscle contraction, commencing within a fewminutes of the barium infusion and lasting 10-15minutes; in 11 animals studied, the increase

BaC12

I ]30g250

J mmHg03500

O

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FIG. 1. The effect of an intravengus infusiont ofbarium chloride (24-5 mg/kg) on indirectly-elicitedtwitches of the gastrocnemius group of muscles(upper record), arterial blood-pressure (middlerecord), and heart-rate (lower record).

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G. D. Schott and B. McArdle

BaC12

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FIG. 2. The effect of an intravenous infusion ofbarium chloride (16 mg/kg) on directly-elicitedtwitches of the tibialis anterior muscle (upper record),arterial blood-pressure (middle record), and heart-rate(lower record). Curarization maintained by intra-venous injections of tubocurarine (0-6 mg/kg), indi-cated by arrows.

ranged from 5-60% (mean 38%) above the basalcontraction amplitude; (2) a partial paralysis,followed by (3) spontaneous recovery. The par-tial paralysis was manifested by a prolongedperiod of reduced contractions, lasting 30 min-utes to more than two hours, in the rats thatrecovered. Of the 11 animals referred to above,seven made a complete or partial recovery, and

in these, the reduced contractions were 30-800Oof the control value (mean 50%0); the otherseither died or failed to demonstrate any recovery,and hence a reasonable state of the preparationcould not be assured.The effective paralysing dose of barium

chloride was found empirically to be 16-25 mg/kg, administered at a rate of 0 5 mg/min. Higherdoses were more often fatal, although fatalitiesstill occurred in the dose range indicated above.Lower doses usually did not result in paralysis.although they would frequently give the firstphase of increased contraction. Death was likelyto occur if the barium was given as a rapid bolus;and prolonged, slow infusion often failed tocause any reduction in muscle contraction. Itwas not possible to correlate the degree ofparalysis with the dose of barium administeredusing this preparation; and it was evident thatthe effective dose was close to the lethal dose.The degree and duration of the phases were

variable. Generally the degree of potentiation ofmuscle contraction during phase (1) was notfound to correlate with the subsequent decreaseof phase (2); and exceptionally, the two phases

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FIG. 3. The effect of an intraveenous infusion of barium chloride (22 mg/kg) on indirectly-elicited maximaltwitches of the gastrocnemius group of muscles, and plasma barium and potassium concentrations.

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were separated entirely by a period of contrac- paralysis, or the cardiovascular events (seetions of basal amplitude. below).

CORRELATION OF PLASMA ION CONCENTRATIONWITH MUSCLE CONTRACTION The plasma sodium,potassium and barium ion concentrations weredetermined concurrently with the amplitude ofmuscle contraction, and an example is shown inFig. 3; the plasma sodium concentration re-mained unchanged at 131-136 mEq/1. There is a

decrease in plasma potassium concentration,which is striking in its degree and rapidity of on-set. The plasma barium concentration during thecourse of the experiment was 5-100 ,ug BaCl2/ml., and, unlike the plasma potassium concentra-tion, did not show a subsequent rise after theinitial fall. The plasma ion concentrations werenot studied during the brief, initial phase of en-hanced muscle contraction; but there is an evi-dent and marked correlation between contrac-tion amplitude and plasma potassium level, acorrelation not observed with the plasma bariumor sodium levels.

In eight animals, the control plasma potassiumconcentration values ranged from 3-9-4-6 (mean4 2) mEq/l. The lowest values of plasma potas-sium concentration attained in five treated ratswhich recovered from barium-induced paralysisranged from 1-8-2-3 (mean 2 0) mEq/l.; and thusbarium reduced the initial plasma potassiumconcentration by about one half.

It should be noted that the blood sampleswere unavoidably replaced with saline to main-tain the fluid volume; it is possible therefore thatthis added saline could give rise to some mis-leading observations of the plasma ion con-

centrations.

EFFECT OF ADRENALECTOMY The possibility thatparalysis might be due to an effect mediatedthrough barium-induced adrenal catecholaminerelease (Douglas and Rubin, 1964) was investi-gated, since adrenaline administration is knownto be associated with an initial hyperkalaemiathat is followed by prolonged hypokalaemia(D'Silva, 1934). Furthermore, administration ofadrenaline may precipitate attacks ofweakness inpatients with familial periodic paralysis (Allottand McArdle, 1938). Bilateral adrenalectomy infour rats did not affect the development of

EFFECT OF PROPRANOLOL The hypokalaemiafollowing the injection of adrenaline noted byD'Silva was subsequently found to be a functionof adrenergic beta-receptor stimulation (Powelland Skinner, 1966; Todd and Vick, 1971; Vicket al., 1972). The ability of a beta-receptor block-ing drug to reverse the paralysis induced bybarium was therefore investigated. Propranololwas given intravenously in a dose of 0 5 mg/kg,a dose sufficient to abolish a fall in blood-pres-sure induced with 0 5-5 Vg/kg isoprenaline.Propranolol in this dose, and also in a consider-ably higher dose of 4-5 mg/kg, failed to reversethe barium-induced paralysis in six animals. Themuscle response was also unaltered when pro-pranolol was given prophylactically 0-30 minutesbefore the barium.

EFFECT OF POTASSIUM CHLORIDE Injection ofpotassium chloride intra-arterially close to thefemoral artery of the dissected leg, in a dose of37-75 mg/kg, resulted in a temporary increase inmuscle contraction elicited indirectly or directly,both before and during barium-induced paralysisin four rats. Though these findings confirm thebeneficial effect of potassium salts, and indeedpotassium could be expected considerably to en-hance contraction in conditions ofhypokalaemia,they provide little information as to the mode ofaction of barium.

EFFECT OF CALCIUM CHLORIDE The effect ofcalcium was investigated, with a particular viewto determining whether 'competition' could bedemonstrated between these two divalent alka-line-earth cations. Calcium chloride, 15 mg/kg,given in a similar way to potassium chloride, andin approximately equimolar amounts to thebarium administered, on one occasion reducedthe contractions ofindirectly-stimulated muscle afurther 10% of that produced by barium. How-ever, in three other instances, it did not alter thecontraction response, even when given in re-peated doses totalling 75 mg/kg over a period ofabout one hour.

EFFECT OF OUABAIN The effect of ouabain wasinvestigated in view of its well-known effects on

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membrane function, in particular its inhibitingeffect on Na+-K+-stimulated ATPase and thesodium pump. Within two minutes of its injec-tion, intravenous ouabain in a dose of 0-5-1U5mg/kg was found unequivocally to reversebarium-induced paralysis of muscles stimulateddirectly or indirectly in four animals. The effectis illustrated in Fig. 4. Given before barium

BaC12 OUABAIN

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10minsFIG. 4. The effect of intravenous ouabain (05 mg/

kg) on the indirectly-elicited maximal twitches of thegastrocnemius group of muscles (upper record) andblood pressure (lower record) ofa rat, treated with an

intravenous infusion of barium chloride (21 mg/kg).Due to limitation of the recording system, only part ofthe potentiation of muscle contraction is seen.

administration, it did not prevent paralysis;moreover, in control, curarized animals, it pro-duced an increase in contraction lasting about 15minutes. When given in small doses (5-10 Ftg/kg),ouabain had no effect on the paralysis.

CARDIOVASCULAR AND GENERAL EFFECTS OF

BARIUM The hypertensive action noted by manyprevious workers (Cathcart and Clark, 1915;Roza and Berman, 1971) was confirmed: theblood pressure rose when even minute amountsof barium had entered the circulation. The bloodpressure sometimes doubled within three min-utes, and the heart-rate fell as the pulse pressurewidened. These effects are illustrated in Figsand 2, where they can be seen in relation to thechanges in muscle contraction. It is evident thatthere is no apparent correlation between thecardiovascular and the muscular events: in par-ticular, hypertension was invariably producedregardless of the presence and degree of paralysis(or increased contraction). Hypertension was

not apparently affected by any of the substancesadministered, nor by adrenalectomy.

Although electrocardiograms were not re-

corded, the presence of arrhythmias could beinferred from observation of the apex beat, theirregular movement of the column of blood inthe carotid cannula, and irregularities producedin the heart-rate record. By these criteria, arrhyth-mias were not infrequently noted 30 minutes toone hour after barium administration, whendeath was most likely to occur. There was noapparent correlation between these arrhythmiasand the development of paralysis.A mucoid diarrhoea and profuse urination,

both well-known effects of barium, were oftenobserved 30 minutes to one hour after bariuminfusion.The lethal effects of barium were considered to

be due to cardiac or respiratory failure, or both.Cardiac failure was often associated with thedevelopment of arrhythmias, but the contribu-tion of other factors, such as the very consider-able hypertension, could not be assessed. Respira-tory failure was probably implicated in thosenon-curarized and non-ventilated animals, inwhich extreme paralysis affecting the respiratorymuscles presumably resulted in ventilatory fail-ure.

DISCUSSION

The administration of barium has for long beenknown to cause skeletal muscle paralysis, aneffect observed both in animal experiments(Orfila, 1816; Cyon, 1866) and in cases of humanpoisoning with barium salts (Huang, 1943;Morton, 1945; Lewi and Bar-Khayim, 1964).The present studies indicate that this paralysis isdue, although not necessarily primarily or ex-clusively, to a direct effect produced by bariumon skeletal muscle.The effect of barium is exceptional, for acute,

transient paralysis with hypokalaemia is not afeature of administration of the other alkaline-earths, calcium or strontium. In this study, thelack of effect of calcium administration on theparalysis produced by barium supports the viewthat simple divalent cation 'competition' is un-likely to be a significant factor.

Since the time course of development ofparalysis correlates well with that of hypo-kalaemia, but not with changes in the plasmabarium concentration, a fundamental role of thepotassium ion may be inferred. It is of consider-

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TABLECOMPARISON BETWEEN SOME FEATURES OF BARIUM POISONING AND HYPOKALAEMIC PERIODIC PARALYSIS

Flaccid paralysis of skeletal muscleDirect muscle involvementRespiratory muscles involvedSmooth muscle involvementConvulsionsSensory involvementReflexesHypertension

Plasma potassium concentration in attackEffect on paralysis of K administrationCardiac involvement:

ArrhythmiasHypo-K ECG

Reported age group predominantly affected

Fatal outcome

Periodic paralysis

YesYesExceptionalNeverNeverNeverReduced or absentVery exceptionalReducedBeneficial

ExceptionalCommonChildren and young

adultsExceptional

Bariuim poisoning

YesYesSometimesAlwaysOccasionalNeverReduced or absentAnimals always,humans sometimes

ReducedBeneficial

FrequentCommonAdults

Frequent:dose dependent

able interest that the paralysis induced by bariumbears striking similarities to the hypokalaemictype of human periodic paralysis. The features ofthe periodic paralyses are well known, and haverecently been reviewed (McArdle, 1969; Pearsonand Kalyanaraman, 1972). It is relevant that inthe hypokalaemic variety the plasma potassiumconcentration falls, often to low levels, in associa-tion with episodes of paralysis; the concentrationtends to return towards normal during recovery,and of course responds to potassium salts ad-ministered in adequate dosage. Some of thefeatures of barium-induced paralysis and hypo-kalaemic periodic paralysis are compared in theTable.Of the many causes of skeletal muscle paraly-

sis, the association with transient hypokalaemia,common to both barium and hypokalaemicperiodic paralyses, is unusual; and some of theways in which such a hypokalaemia in bariumpoisoning could arise and its possible significanceto paralysis will therefore be considered.

That urinary loss cannot account for thelowered plasma potassium concentration hasbeen demonstrated by Roza and Berman (1971),and furthermore the rapid lowering and subse-quent restoration of the plasma potassium con-centration makes urinary (or faecal) potassiumloss most unlikely as a relevant factor. An effectdue to dilution is also considered improbable,since the plasma sodium concentration remainsessentially unchanged. It would appear reason-

able to speculate that the hypokalaemia could beaccounted for by increased potassium uptakeinto the muscle cell, especially since potassiumuptake into the erythrocytes of barium-treateddogs has been shown to occur (Roza andBerman, 1971).A more detailed consideration of the ways in

which such an increase in intracellular potassiumconcentration with hypokalaemia could occurmay be outlined. (1) Barium-induced stimula-tion of adrenergic beta-receptors could causehypokalaemia, since, as has been discussedabove, stimulation of these receptors is known tocause increased intracellular potassium uptake.Such an effect is considered unlikely, sincepropranolol did not affect the paralysis inducedby barium. Moreover, the lack of effect ofadrenalectomy in these present experiments fur-ther suggests that catecholamines, at least ofadrenal origin, play little or no part in the pro-duction of paralysis, although barium greatly in-creases adrenal catecholamine secretion (Douglasand Rubin, 1964). (2) Insulin and glucose ad-ministration is well known to be associated withintracellular potassium uptake, and barium, atleast in certain in vitro experiments, can replacethe necessary role of calcium in glucose-stimula-ted insulin release (Hales and Milner, 1968); thisis unlikely to be a causative mechanism in theproduction of paralysis, since even large doses ofinsulin are associated with paralysis only inexceptional conditions, such as occasionally arise

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during the treatment of diabetic coma. Thepeculiar susceptibility of patients with hypo-kalaemic periodic paralysis to the developmentof paralysis on administration of insulin andglucose is of interest in this context. (3) Potassiumefflux from cells could be relatively reduced bybarium, causing in time an effective retention ofintracellular potassium. It may be relevant thatpatients with hypokalaemic periodic paralysiscan often prevent an attack of paralysis by under-taking moderate exercise, possibly by inducingthe loss of potassium that normally occurs onexercise (Grob et al., 1957). Barium might act bypreventing potassium efflux, since it is wellknown from electrophysiological experiments toreduce potassium fluxes across, among others,muscle cell membranes (Volle, 1970; Hendersonand Volle, 1972). The effect on potassium fluxesmay perhaps be due to the similarity in size be-tween the crystal radii of the potassium andbarium ions, although any reduction in potas-sium fluxes would have to affect the effluxmore than the influx. (4) The hypokalaemiacould be secondary to changes in intracellularmetabolism. For instance, potassium uptakecould be related to changes in carbohydratemetabolism, or to any increase in intracellularnegativity. (5) Disturbance in cell membranefunction is a further possibility that may be con-sidered. In circumstances where the membraneNa +-K + -stimulated ATPase activity is en-hanced, excess intracellular potassium couldaccumulate, as has been demonstrated in workon high and low potassium-containing erythro-cytes of certain animal species (Christinaz andSchatzmann, 1972). Whether barium enhancesthis membrane ATPase activity is at present con-troversial: although enhancement was initiallydemonstrated on cultured myocardial cellNa +-K + -stimulated ATPase (Henn and Spere-lakis, 1968), the enzyme system was subsequentlyfound to be more complex than had previouslybeen thought (Sperelakis and Lee, 1971). Thepotentiating effect of ouabain in suitable dosageson muscle contraction is well known (Faust andSaunders, 1957). Although the effect of ouabainin the present experiments could be accountedfor by inhibition of the Na +-K + -stimulatedATPase, and resultant loss of intracellularpotassium, in view of the very many and non-selective effects that ouabain can produce under

in vivo conditions, such a hypothesis must atpresent remain entirely speculative.The relationship of the hypokalaemia to the

paralysis induced by barium is poorly under-stood, as indeed it is in hypokalaemic periodicparalysis. Furthermore, it should be pointed outthat the changes in plasma potassium concentra-tion could be entirely secondary to other effectsof barium and unrelated aetiologically to theparalysis. Data concerning changes in the restingmembrane potential in in vivo barium poisoningare at present unavailable, but the unexpectedfindings in hypokalaemic periodic paralysis thatthe in vivo resting potential is unchanged (Shy etal., 1961) or reduced (Riecker and Bolte, 1966),despite theoretical predictions that hyperpolariza-tion should occur, may be recalled.Numerous other factors that are likely to be

highly important may have to be taken intoaccount. Many such factors have been con-sidered, and in some instances explored, in thecase of hypokalaemic periodic paralysis, andinclude: the form (free, bound, or compartment-alized) in which intracellular potassium mightexist; whether the concentration or only the con-tent of potassium is increased (Shy et al., 1961);the role of sodium and calcium ions; the relation-ship of the membrane potential to the contractileresponse (Merton, 1956); whether more than onetype of potassium channel is involved; changesin muscle cell diameter and hence in membraneproperties; the function of the sarcoplasmicreticulum; and changes in intracellular metabol-ism.

Although certain of these factors have beeninvestigated in periodic paralysis, the aetiologyof this disease has remained elusive. The presentfinding of the direct paralysing effect of bariumon muscle, associated with hypokalaemia, lendssupport to the observation of Huang (1943) ofthe similarity between barium poisoning andperiodic paralysis. It is possible that the uniqueproperties of barium could provide an experi-mental model for the study of certain aspects offamilial periodic paralysis.

The authors are most grateful to Professor W. D. M.Paton, F.R.S. for valuable guidance, Dr. AnneWarner for helpful discussion, and Dr. B. V.Robinson and Mr. P. J. Morrison for technicaladvice. This work forms part of a MD dissertation

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submitted to the University of Cambridge by G.D.S.,who is also indebted to the Charles E. Merrill Trustfor financial support.

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Cathcart, E. P., and Clark, G. H. (1915). The action of bariumchloride on the vascular system. Journal of Physiology, 50,119-127.

Christinaz, P., and Schatzmann, H. J. (1972). High potassiumand low potassium erythrocytes in cattle. Journal ofPhysiology, 224, 391-406.

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