Postgraduate Medical Journal (January 1971) 47, 36-43.

Experimental approaches to the prophylaxis and treatment ofischaemic heart disease

J. D. FITZGERALDM.B., M.R.C.P.

Head of Pharmacology, Imperial Chemical Industries,Mereside, Alderley Park, Macclesfield, Cheshire

SummaryThis paper describes some of the basic hypotheses onwhich our research in the cardiovascular field has beenbased. The difficulties and .'shortcomings of theexperimental models used and our reliance on guidancefrom clinical science has been emphasized. The proper-ties, effects and mode of action of the drugs resultingfrom our cardiovascular research have been described.

IntroductionThe purpose of this paper is to describe our re-

search aims and their implementation in the field ofischaemic heart disease. The research programme isdivided into two areas. Firstly, the discovery of ameans of controlling the development of coronaryartery disease, and secondly the devising of agents

that would control the complications of establishedcoronary artery disease (Fig. 1). There are tworequirements for effective research in the field ofcoronary artery disease. In the first instance, thereis a need for reliable animal models of the disease andits complications. Whilst many forms of experi-mental atherosclerosis are available, their relevanceto the human disease is debatable, particularly inrelation to the development of therapeutic agents.The second requirement is an agreed understandingof the pathogenesis of coronary artery disease andits attendant complications. Unless clinicians candelineate realistic therapeutic goals, based on aknowledge of the causative mechanisms underlyingthe disease, then experimental research may easilyproceed along misguided lines.

Research approaches

Complications ProphylIxs(a )Angina pectoris(b)Myocardial infarction

i.arrhythmiasii.'pump failure '

prevention of plaqueformation

- (? Thrombogenic)_ (? Hyperlipidemic)

FIG. 1. The basis of the separation of experimental research in ischaemic heart disease.

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Experimental approaches to ischaemic heart disease

Prophylaxis of coronary artery diseaseThe experimentalist in this field is in the difficult

position of wishing to devise an experimental modelto test synthetic substances whilst there is disagree-ment as to what a particular animal model reallymeans in terms of human disease, what therapeutictarget is worthwhile, and what type of agent mightbe devised to achieve such a target. Whilst themechanism of formation of the atheroscleroticplaque is debatable, clinical and epidemiologicalresearch suggests that certain factors predispose toplaque formation (Katz & Stamler, 1953). Anobvious approach to the problem of the athero-sclerotic plaque could be to delineate all the factorsthat favour its growth, and attempt to attenuate oreven reverse the trend. In 1955, when our research inthis field started, the factor that was most widelyconsidered worthy of control was elevated serumlipids, particularly serum cholesterol. The associationbetween hyperlipidaemia and ischaemic heart diseaseis based on four types of observation: (1) thatarterial lesions contain lipid, (2) that induced hyper-lipidaemia in animals leads to arterial lesions richin lipids, (3) that patients with the symptom complexof ischaemic heart disease often have abnormalserum lipid levels, and (4) that hypercholesterolaemiaat least is associated with increased risk of developingischaemic heart disease (Oliver, 1967a). At that time,our research aim, therefore, was to discover an agentthat would lower serum cholesterol and triglycerideseffectively, and cause no serious side effects. Such anagent should meet most of the following require-ments: (a) it should have a sustained and consistenteffect in reducing elevated serum cholesterol and tri-glycerides or more correctly, it should consistentlylower the SFo-20 and SF20 400olipoprotein fractions, (b)this lowering of the serum lipids should be associatedwith a lowering of the accumulation of lipids intissues, (c) there should be an increase in the excre-tion of neutral sterols in the stool, (d) the agentshould not alter the patient's way of living, (e) thereshould be few toxic effects associated with theachievement of the hypolipidaemic action, (f) thereshould be few side-effects, (g) precursors of choles-terol should not accumulate in the body, (h) anunderstanding of the mode of action of the drug isnecessary. The reason for laying down such stringentrequirements is that the final aim of treatment may beto give the agent to healthy hyperlipidaemic indi-viduals who are assumed to have a greater than usualrisk of developing vascular disease and who maytherefore need to take the drug for the rest of theirlives.More recently, additional requirements have been

laid down. In addition to demonstrating that an* Clofibrate ('Atromid-S'-IC1) is the ethyl ester of chloro-phenoxyisobutyric acid (CPIB).

agent must lower elevated serum lipids effectivelyand safely, it is necessary to show that, if it is givenin the pre-symptomatic or established phases ofischaemic heart disease, it alters the mortality fromcoronary heart disease. Some knowledge of its effecton the atherosclerotic plaque is also necessary.

Clofibrate*Clofibrate meets many of the requirements laid

down above, though naturally answers are stillawaited from many of the studies with this com-pound. The activity of clofibrate was discovered in1955 by Thorp, whilst examining a series of aryloxyisobutyrates with the following basic chemicalstructure (Fig. 2). Thorp showed that they all possessa novel type of hypolipaemic activity in experimentalanimals (Thorp, 1955). In normal rats and dogs theserum cholesterol was lowered by 60-70% com-pared to that of controls, following administrationof these compounds, and the response was main-tained for as long as the compound was administered.The cholesterol returned to normal levels on stoppingtreatment. Initially, therefore, the testing procedurewas simply to determine the effect of these drugs onserum cholesterol in a variety of animals. One com-pound, the p-chlorophenol aryloxyisobutyric acid(CPIB*) was selected for clinical evaluation. Studiesin monkeys showed that the addition of androsteronepotentiated the hypolipidaemic action of CPIB andtherefore the first studies in man were carried outwith clofibrate in combination with androsterone.Subsequently, it was found that an equivalent hypo-lipidaemic effect could be achieved in man withoutthe addition of androsterone (Oliver, 1963).The effect of CPIB in man is to reduce elevated

levels of serum lipoproteins, particularly the SF20 -400fraction and to a lesser extent the SFO2_ fraction.Studies in a mixed population of patients withcoronary artery disease show that elevated serum

Structure of aryloxyisobutyrates

RI CH3 R2

[ary 1] '0 C COO EALKYL]

CH3Clof!brate - Chemical structure

FIG. 2. The structure of aryloxyisobutyrates and clo-fibrate.

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38 J. D. Fitzgerald

cholesterol levels are reduced by 15-30% and ele-vated serum triglyceride levels by 30-40°% (Oliver,1967b). These effects persist for as long as treatmentcontinues, and no escape is observed in patients whorespond adequately. In addition, clofibrate reducesalimentary lipaemia, and increases lipoprotein lipaseactivity (Hood, Bedding & Corlander, 1963). Serumfree fatty acids are lowered, but are still responsive tocatecholamine stimulation. Clofibrate does not causeaccumulation either in blood or tissues ofunsaturatedprecursors of cholesterol such as desmosterol, and itbrings about a reduction in the total cholesterol pool(Nestel, Hisch & Couzens, 1965; Hellman et al.,1963). This is accompanied by an increased biliaryexcretion of neutral sterols (Mitchell, Truswell &Brontestewart, 1967). Raised plasma fibrinogen isreduced by clofibrate, and decreased fibrinolyticactivity is enhanced. Platelet stickiness, platelet turn-over and platelet survival times are altered towardsnormal values (Oliver, 1967b). In clinical terms, visibletissue deposits such as lipaemic exudates in the retinaof diabetics with retinopathy, or skin xanthomatamay regress following treatment with clofibrate for6-12 months (Duncan et al., 1968; Mishkel, 1967).The initial regression may be achieved without amarked reduction in the serum cholesterol, whichsuggests that it may take several months to reduce alarge cholesterol pool. Oliver (1967) has suggestedthat the principal indications currently for the use ofclofibrate are (1) patients with hypercholesterolaemiaand hypertriglyceridaemia with or without xantho-mata, (2) patients with fasting latescent plasma, (3)patients with hypercholesterolaemia with or withouta familial predisposition to vascular disease, (4) dia-betic patients with lipaemic diabetic retinopathy,

in order to prevent further deterioration in visualacuity.

Mode of action of clofibrateAny explanation of the mode of action of clo-

fibrate must take into account the following observa-tions. (1) Clofibrate does not decrease cholesterolsynthesis in the liver when added to liver slices invitro. This suggests, therefore, that it does not have adirect action on cholesterol synthesis at the hepaticlevel (Avoy, Swyrd & Gould, 1965; Thorp &Waring, 1962). (2) Clofibrate does not lower serumcholesterol in animals which have been thyroidec-tomized (Westerfeld, Richert & Ruegamer, 1968).(3) The volume distribution of CPIB shows that96-98%5 is confined to the albumin space which is8-125/ of the total body weight. It is bound to theanionic binding sites of albumin. (4) In experimentalanimals, CPIB is not detected in hepatic bile, andmost of an oral dose is excreted in the urine as theglucuronide (Thorp, 1963). The problem, therefore,is to explain how an organic acid that is fully ionizedin plasma, and is highly albumin-bound, that isexcreted as the glucuronide via the kidney and is notmetabolized in the body, can exert such a widevariety of effects (Fig. 3). The multi-system of effectsof CPIB can be explained on the hypothesis thatphysiologically important albumin-bound endo-genous acids are displaced from albumin by CPIB.Thus the continuous administration of CPIB resultsin a new equilibrium state in which these endogenousacids are either displaced to weaker ionic bindingsites on albumin, or displaced altogether fromalbumin to cause a small increase in the concentra-tion of 'free form' in the circulation. The free form

Clofibrate CH3 CH3

Experimental approaches to ischaemic heart disease

of these substances is responsible for their physio-logical effects. Physiologically important substancesthat are bound to albumin, which have been shownto be displaced by clofibrate, are thyroxine and itsmetabolites, free fatty acids, and 17-ketosteroid sul-phates as well as pyridoxal phosphate and tryptophan.There is much experimental work to support this

hypothesis.

Clofibrate and thyroxineChang et al. (1967) have confirmed that clofibrate

depresses the thyroxine binding to human pre-albumin at a concentration of 6 x 10- 3 M. Thyroxine-binding globulin is unaffected. Studies by Thorp(Thorp & Waring, 1962), and more recently byWesterfield et al. (1968) have shown that clofibrateincreases the concentration of radio-labelled thyrox-ine in the rat liver by 40%/. There is no increase inthe metabolic rate or alteration in thyroid functionin these rats. In the thyroidectomized rat, the actionof clofibrate on serum cholesterol is abolished.Furthermore, it has been shown that in the rat, themaximal effect of CPIB on the serum cholesterolcorresponds with the period of maximal thyroidadrenocortical function. Clofibrate causes an increasein the weight of the liver in the rat and monkey,which is due to increased synthesis of hepaticprotein. This is accompanied by a reduction inhepatic glycogen (Platt & Thorp, 1966). Thesechanges are identical with those observed whenthyroxine alone is administered. Studies by Harrison& Harden (1966) in hypercholesterolaemic patientswith severe myxoedema showed that the serumcholesterol was unaffected by clofibrate until a smallsupplement of thyroxine is added. The hypolipid-aemic effect of thyroxine treatment is significantlyenhanced by the simultaneous administration of clo-fibrate. If thyroxine alone is subsequently with-drawn, a rebound of serum cholesterol to the pre-treatment level, or higher, occurs.Apart from its effects on thyroxine distribution,

clofibrate also reduces the transport of free fattyacids from the fat organ to the liver. Barrett inour laboratories has shown that in vitro, CPIB willreduce the rate of free fatty acid release from epi-didymal fat pads incubated in plasma, as well asreduce the peak levels of free fatty acids following theinjection of adrenaline and noradrenaline (Barrett,1969a). It also abolishes the increase in cholesteroland phospholipids following ACTH stimulation indogs. These observations suggest that part of thehypolipidaemic action of CPIB is due to depressionof free fatty acid transport (Thorp, personal com-munication).

In summary, it seems that clofibrate acts pri-marily by displacing physiologically important sub-stances from anionic binding sites on albumin. As a

result, there is an increased uptake of thyroxine bythe liver. The increased hepatic thyroxine activitycauses an increase in protein synthesis. The accom-panying reduction in hepatic glycogen increases thehepatic requirement for an alternative energy sub-strate, i.e. free fatty acids. However, in the presenceof clofibrate, there is a depression of circulating freefatty acid levels. The combined effects ofa diminishedsupply of free fatty acids to the liver and an increasein concentration of hepatic thyroxine, results in amarked drop in circulating levels of SF20 400 lipo-proteins which is the most marked and consistenteffect of clofibrate in man. This summary of themode of action of clofibrate is almost certainly in-complete. Space does not permit a consideration ofthe possible role of other important substances suchas pyridoxal phosphate, androsterone sulphate, de-hydroepiandrosterone sulphate and tryptophan.

Subsequent developmentsSome scepticism exists in regard to this view of the

mechanism of action of clofibrate. If the theory istrue, then it should be possible to discover otheragents which also lower serum lipids because theydisplace physiologically active substances fromalbumin. In the past 5 years, our experimentalapproach to the lowering of serum lipids has been totest drugs in vitro. A search was made for compoundsdisplaying a greater selectivity and intensity of effecton the binding of thyroxine to albumin and pre-albumin than that of clofibrate. Furthermore, wewished to discover compounds with a greater degreeof persistence in vivo than clofibrate, so that a lowerdaily dosage could be used. The first tests consistedof studies of the water solubility and half-life, in therat, of candidate compounds of the aryloxyiso-butyrate series. It was found that diminished watersolubility was accompanied by an increase in thein vivo half-life.

Experiments were then carried out to determinethe effects in vitro of selected compounds on thealbumin binding of thyroxine. It was found that thecompound ICI 54,856 was more effective than CPIBin increasing the amount of free thyroxine in anin vitro albumin-thyroxine system.

CH3

CI C- COOH

CH3

The methyl ester of ICI 54,856 has been takenforvard for both animal and human studies. Itsaction is similar to that of clofibrate, but because ofits increased persistence, it is effective at about

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1/100th of the dose of clofibrate in lowering bloodcholesterol in rat, dog and man. Its half-life in manis 30-40 days. An effective dose in man is 0 1 mg/kg,giving a circulating level of 60 ,±g/ml. 60-90% ofICI 54,856 is excreted by the kidney, partly as thefree acid and partly as the glucuronide conjugate.Preliminary clinical trials with this novel compoundshow that it not only lowers the SF20 -100 lipoproteinfraction effectively, but also the SFo020 fraction,which in certain cases is resistant to CPIB treatment.(Barrett, 1969a). This drug is, however, in very earlystages of clinical evaluation, and it is still in theexperimental phase. It illustrates how an understand-ing of the mode of action of a drug can lead to furtherdiscoveries and that careful in vitro studies can be ofpredictive value for drug action in man.

The treatment of the complications of coronary arterydiseaseAngina pectorisThere is no animal model for the study of angina

pectoris, because it is a symptom and therefore ispeculiar to man. Any experimental approach mustbe related to clinical experience. It is widely acceptedthat anginal pain results from a disproportionbetween myocardial work and myocardial oxygensupply. Most experimental effort in the past has beendevoted towards developing therapeutic agents whichwill increase myocardial blood flow. Whilst sub-stances with potent dilating effects have been found,their clinical success appears to have been limited.Unless the obstruction to blood flow in diseasedcoronary arteries can be removed, it is probably morerational to attempt to improve the mechanicalefficiency of the pump, rather than to improve bloodflow through diseased arteries. All therapy for anginapectoris aims at reducing the work of the heart for agiven external work-load, and no drug has beendiscovered that permits more total cardiac work tobe done before pain. Thus, both weight-loss andtrinitrin exert their beneficial effects in angina bydiminishing the work of the heart. Initially, trinitrinwas thought to act primarily by coronary vasodilata-tion, but this is not now considered to be the primarymode of action (Gorlin et al., 1959). Cervical sym-pathectomy also lowers the work of the heart asshown by Apthorp, Chamberlain & Hayward(1964). In their group of eight anginal patients whounderwent bilateral cervical sympathectomy forsevere angina pectoris, several patients increasedtheir exercise tolerance two to three-fold followingthis operation. Similarly, Lindgren (1950) hasreviewed the effects of cervical sympathectomy ineighty anginal subjects, and shown that 52%° showedmarked or moderate improvement through thisoperation.

These studies emphasize the role of endogenouscatecholamines in increasing cardiac work.

Black in our laboratories initiated studies aimedat specifically interfering, by chemical means,with catecholamine activity on the heart. It washoped that an agent could be discovered whichwould diminish the effects of catecholamines in in-creasing cardiac work in those patients with impairedmyocardial blood supply (Black, 1967). A clue as tothe type of chemical structure to be sought was pro-vided by the discovery of Powell & Slater (1958), thatthe dichloro analogue of isoprenaline would blockthe effects of catecholamines on the heart. Thoughdichloroisoprenaline was introduced to clinicalstudies, there is no evidence that it was studied inangina pectoris. Thus it was Black's hypothesiswhich really provided the impetus rather than thediscovery of dichloroisoprenaline. The first effectiveagent discovered was pronethalol ('Alderlin', ICI).It was introduced into clinical trial specifically todetermine whether an agent which prevented theaction of catecholamines on the heart would be ofbenefit in angina pectoris (Black & Stephenson,1962). It was shown to increase exercise tolerance inangina pectoris, and also to improve the anginalstate clinically (Dornhorst & Robinson, 1962;Alleyne et al., 1963) Subsequently, pronethalol waswithdrawn because it was found to cause lympho-mata in the thymus of certain strains of mice. Itwas replaced by propranolol ('Inderal', ICI) whichhas a different chemical structure and is more potent(Black, Duncan & Shanks, 1965).

Mode ofaction in angina pectorisStimulation of cardiac beta-receptors results in an

increased rate and force of myocardial contraction,as well as speed of conduction within the heart. Asa result there is an increase in the oxygen consump-tion of the heart. In the healthy heart, blood flow tothe myocardium is not a limiting factor, and there-fore the heart is able to increase its work withoutincurring any damage. However, where the bloodsupply is limited, then there is reason to supposethat benefit may accrue from attenuating changes inthe rate and force of myocardial contraction.Themode of action of propranolol in reducing card-

iac work is complex. The more important features are:(1) reduction in heart rate, (2) reduction in thespeedofmyocardial fibre shortening, (3) possibly a reductionin after-load. All these effects will reduce myocardialoxygen demand. They may be offset if the heartincreases in size, as is associated with cardiac slowingand a reduction of myocardial contractility. Further-more, there may be an increase in the systolic ejectiontime. An increase in either of these parameters willincrease myocardial oxygen demand. It is thus notpossible to predict which action will predominate in

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an individual patient, so that some will improve andothers may not (Fig. 4). Intensive study of pro-pranolol in angina pectoris indicates that manypatients with angina pectoris improve their exercisetolerance, reduce their daily incidence of anginalpain, and diminish their requirements for glyceroltrinitrate (Amsterdam, Wolfson & Gorlin, 1968;Gianelly et al., 1967; Ginn & Orgain, 1966).

It has been suggested that propranolol works inangina pectoris by a means other than beta-receptorblockade (Grandjean, 1967; British Medical Journal,1969). Propranolol possesses the additional pharma-cological property of membrane-stabilization "orlocal anaesthesia (Vaughan Williams, 1966; Fitz-gerald, 1960). Hence, it has been suggested that thisproperty, by causing non-specific myocardial de-pression, will improve the anginal state. Clinicalevidence that this is not so has been provided by thestudy of Robinson's group in St George's Hospital(Wilson et al., 1969). They have compared thedextro-isomer of propranolol which has equivalentmembrane-stabilizing properties, but no beta-block-ing properties, with racemic propranolol, whichpossesses both properties. They showed that dexpro-pranolol, like saline, did not increase exercisetolerance in eight anginal patients, whilst racemicpropanolol did do so. It is now very probable thatthe possession of membrane-stabilizing properties isirrelevant to the mode of action of racemic pro-pranolol in the clinical dose range in which it is used(Barrett, 1969; Fitzgerald, unpublished observa-tions).Once the clinical effectiveness of propranolol had

been established, the problem then arose as to what

Positive Neaative

FIG. 4. Schematic representation of wanted and un-wanted haemodynamic effects of beta blocka de in anginapectoris.

further discovery would be clinically desirable.Propranolol blocks other clinically important beta-receptors, particularly those in the lung and thosesubserving certain metabolic responses. A legitimatetherapeutic aim might be an increase in selectivity ofactivity, so that only beta receptors in the heart wereblocked. Furthermore, a compound might be dis-covered which possessed no membrane stabilizingor local anaesthetic properties. In order to discoversuch a compound, the following screening procedurewas employed. Initially all candidate drugs werestudied for their effects in antagonizing isoprenalineon the heart, peripheral blood vessels and lungs.The aim of these primary tests was to separate aneffect on the heart from the effects on the lung andblood vessels. If a likely compound was found, it wasthen studied for its effects on the spike potential inthe isolated frog nerve and also for its effects onintra-cardiac conduction. If the candidate compoundstill seemed interesting, its effects on lipolysis of theepididymal fat pad and on blood lactate levels werealso studied. In addition, its possible effects ondigitalis and halothane-catecholamine arrhythmiaswould be studied at this time. Such procedures areclearly far removed from the clinical situation, andtheir justification is based on a series of assumptions,some of which may be regarded as very tenuous.

PractololBy such procedures, a new beta blocking com-

pound, practolol ('Eraldin', ICI), was discovered.This compound is cardio-selective and has no mem-brane-stabilizing properties. It also differs frompropranolol in that it has a degree of intrinsicstimulant activity. Practolol has a half-life in man of10 hr compared with 2 hr for propranolol, and isminimally metabolized in man, whereas propranololis extensively metabolized (Barrett et al., 1968; Dun-lop & Shanks, 1968; Fitzgerald & Scales, 1968).Practolol has been undergoing clinical evaluation forsome 2 years, and has already been shown to in-crease exercise tolerance in angina pectoris as well asto reduce the consumpton of glycerin trinitrate andthe incidence of anginal pain. These observations areof considerable academic interest, since they confirmBlack's original view that sympathetic activity maybe deleterious to the heart of patients with anginapectoris. They also show that the membrane-stabilizing properties of propranolol are not neces-sary for its action in angina pectoris, since practololis as effective as propranolol in increasing exercisetolerance, but does not have any local anaestheticaction (Wilson et al., 1969).

Other clinical indicationsClinical situations in which propranolol has been

shown to be of value are given in the accompanying

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TABLE 1. Clinical indications in which beta-blockade has been used

Cardiac Endocrine Central nervous Other

Angina pectoris Thyrotoxicosis Parkinsonism GlaucomaArrhythmias Phaeochrom ocytomaHypeitension Certain anxiety statesFallot's tetralogyHypertrophic obstructive cardiomyopathyHyperkinetic heart syndrome

table. Black has indicated that none of these waspredicted from the initial experimental studies inanimals (Black, 1967). This indicates yet again thetremendous value of accurate clinical observationand feed-back of these observations to the laboratoryas a guide for further research. However, Black didpredict that beta-blockade might be of value in thecardiac arrhythmias associated with myocardialinfarction, since it was already known that this was asituation associated with high concentration ofcatecholamines in an area of local tissue necrosis oranoxia. Such a situation is known to be potentiallyarrhythmogenic, and studies over the last 10 yearshave indicated the high incidence of cardiac arrhyth-mias following myocardial infarction. Initially,studies with propranolol indicated that it wouldcontrol or reverse cardiac arrhythmias in myocardialinfarction, but subsequent extensive study both withpropranolol and oxprenolol show that if the drugsare given routinely to patients with myocardial in-farction they have no effect on the morbidity ormortality associated with this condition (Sowton,1968). These observations proved to be very dis-appointing, since there had been considerable hopesthat the prophylactic administration of a beta-blocking drug might diminish the initial high mor-tality due to cardiac arrhythmias in myocardial in-farction, because animal investigations had shownthat beta-blockade would protect against ventriculararrhythmias in experimental myocardial infarction(Fearon, 1967; Pentecost & Austen, 1966).

Myocardial infarction is associated with a state ofhigh autonomic tone, and beta-blockade in thissituation may affect the patient adversely for tworeasons. Firstly, removal of sympathetic activity willpermit vagal dominance of the heart, resulting ininappropriate cardiac slowing, a fall in cardiac out-put, hypotension and shock. The important role ofthe vagus in this situation has been demonstrated byStannard, Sloman & Sangster (1968), who gaveatropine at the same time as propranolol, and pre-vented the unwanted haemodynamic sequelae. Inaddition, severely affected hearts may require in-creased sympathetic activity to maintain a satisfac-tory degree of myocardial contractility. Blockade of

erAanced sympathetic activity in this situation mayreduce myocardial contractility below a criticallevel. It seems, therefore, that the original laboratorypredictions for beta-blockade in cardiac arrhythmiasassociated with myocardial infarction have not beenfulfilled. However, cardiac arrhythmias associatedwith anaesthesia, thyrotoxicosis, phaeochromo-cytoma, exercise and several other states, have beenshown to respond favourably to beta-blockade(Gibson & Sowton, 1969). Recent studies with thecardio-selective beta-blocker, practolol, in post-infarction arrhythmias suggest that this compoundmay be of more value and safer to use in this par-ticular situation, but much clinical study is yet to bedone before such a conclusion can be proven (Jewitt,Mercer & Shillingford, 1969).

AcknowledgmentsI have contributed little to the work described in the paper.

Almost all of it has arisen from the studies of Dr A. M.Barrett, Dr J. Black, and especially Mr J. Thorp. Theirs is thework described in this paper, and I wish to express mygratitude to them for making it so freely available to me.

ReferencesALLEYNE, G.O., DICKINSON, C.J., DORNHURST, A.C.,FULTON, R.N., GREEN, K.G., HILL, I.D., HURST, P.,LAWRENCE, D.R., PILKINGTON, T., PRICHARD, B.N.C.,ROBINSON, B. & ROSENHEIM, H.L. (1963) Effect of pro-nethalol in angina pectoris. British MedicalJourral,2, 1226.

AMSTERDAM, E.A., WOLFSON, S. & GORLIN, R. (1968) Effectof therapy on survival in angina pectoris. Annals of InternalMedicine, 68, 1151.

APTHORP, G.H., CHAMBERLAIN, D.A. & HAYWARD, C.W.(1964) The effects of sympathectomy on the electrocardio-gram and effort tolerance in angina pectoris. British HeartJournal, 26, 218.

Avoy, D., SWYRYD, E.A. & GOULD, R.G. (1965) Effects ofa p-chlorophenoxyisobutyryl ethyl ester (CPIB), with andwithout androsterone on cholesterol biosynthesis in ratliver. Journal of Lipid Research, 6, 369.

BARRETT, A.M. (1969a) Mode of action of clofibrate inrelation to plasma free fatty acid. International Journalof Clinical Pharmacology, Suppi. 1, 29.

BARRETT, A.M. (1969b) Management of coronary arterydisease. British Medical Journal, 1, 318.

BARRETT, A.M., CROWTHER, A.F., DUNLOP, D., SHANKS,R.G. & SMITH, L.H. (1968) Cardio-selective beta-blockade.Archives of Experimental Pathology and Pharmacology,259, 150.

by copyright. on June 1, 2021 by guest. P

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j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.47.543.36 on 1 January 1971. Dow

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http://pmj.bmj.com/

Experimental approaches to ischaemic heart disease 43

BLACK, J.W. (1967) The predictive value of animal tests inrelation to drugs affecting the cardiovascular system inman. Drug Responses in Man (Ed. by C. Wolstenholme andR. Porter), pp. 113, 121-2. Churchill, Lcndon.

BLACK, J.W., DUNCAN, W.A.M. & SHANKS, R.G. (1965)Comparison of some properties of prenethalol andpropranolol. Briiish Journal ofPharmacology, 25, 577.

BLACK, J.W. & STEPHENSON, J.S. (1962) Pharmacology of anew adrenergic beta-receptor blocking compound (Netha-lide). Lancet, ii, 31 1.

BRITISH MEDICAL JOURNAL (1969) Management of coronaryartery disease. British Medical Journal, 1, 37.

CHANG, Y.H., PINSON, R. & MALONE, M.H. (1967) Displace-ment of L-thyroxine from its binding proteins in human,dog and rat plasma by a p-chlorophenoxyisobutyric acid.Biochemical Pharmacology, 16, 2053.

DORNHORST, A.C. & ROBINSON, B.F. (1962) Clinical pharma-cology of a new beta-adrenergic blocking agent (Netha-lide). Lancet, ii, 314.

DUNCAN, L.J.P., CULLEN, J.F., IRILAND, J.T., NOLAN, J.,CLARKE, B.F. & OLIVER, M.F. (1968) A three-year trial ofAtromid therapy i n exudative diabetic reinopathy.Journal of ahe American Diabetes Association, 17, 458.

DUNLOP, D. & SHANKS, R.G. (1968) Selective blockade ofadrenoceptive beta receptors in the heart. British Journalof Pharmacology, 32, 201.

FEARON, R.E. (1967) Propranolol in the prevention ofventricular fibrillation due to experimental coronaryartery occlusion. Observations on its mode of action.American Journal of Cardiclogy, 20, 222.

FITZGERALD, J.D. (1960) Perspectives in adrenergic betareceptor blockade. Clinical Pharmacologj and Thera-peutics, 10, 292.

FITZGERALD, J.D. & SCALES, B. (1968) Effect of a newadrenergic beta blocking agent (ICI 50,172) on heart ratein relation to its blood levels. International Journal ofClinical Pharmacology, 1, 467.

GIANELLY, RE., GOLDMAN, R.H., TREISTER, B. & HARRISON,D.C. (1967). Propranolol in patients with angina pectoris.Annals of Internal Medicine, 67, 1216.

GIBSON, D. & SOWTON, E. (1969) Beta adrenergic blockingdrugs in dysrhythmias. Progress in Cardiovascular Diseases,12, 16.

GINN, W.M. JR & ORGAIN, E.S. (1966) Propranolol hydro-chloride in the treatment of angina pectoris. Journal of theAmerican Medical Association, 198, 1214.

GORLIN, R., BRACKFELD, N., MACLEOD, C. & Bopp, P. (1959)Effect of nitroglycerine on the coronary circulation inpatients with coronary artery disease or increased leftventricular work. Circulation, 19, 705.

GRANDJEAN, T. (1967) The effect of adrenergic beta blockadein angina pectoris. Schweizerische Medizinische Wochen-schrift, 97, 1559.

HARRISON, M.T. & HARDEN, R.M.C.G. (1966) Some effectsof clofibrate in hypothyroidism and on the metabolism ofthyroxine. Scottish Medical Journal, 11, 213.

HELLMANN, L., ZUMOFF, B., KESSLER, G., KARA, E., RUBIN,I.L. & ROSENFELD, R.S. (1963) Reduction in cholesteroland lipids in man by ethenyl p-chlorophenoxyisobutyrate.Annals of Internal Medicine, 59, 477.

HOOD, R., BEDDING, F. & CORLANDER, B. (1963) a lipopro-tein, lipoprotein lipase and Atromid. Journal of Athero-sclerosis Research, 3, 509.

JEWITT, D.E., MERCER, C.J. & SHILLINGFORD, J.P. (1969)Practolol in the treatment of cardiac dysrhythmias due toacute myocardial infarction. Lancet, ii, 227.

KATZ, L.N. & STAMLER, J. (1953) Experimental Athero-sclerosis. Thomas, Springfield, Illinois.

LINDGREN, J. (1950) Angina pectoris. A clinical study withspecial reference to neurosurgical treatment. Acta MedicaScandinavica, Suppl. 243.

MISHKEL, M.A. (1967) The diagnosis and management of thepatient with xanthomatosis. An experience with thirty-fivecases. Quarterly Journal of Medicine, 107, 141.

MITCHELL, W.V., TRUSWELL, A.S. & BRONTESTEWART, B.(1967) The effect of Atromid S on faecal neutral steroidsand bile acids. Progress in Biochemical Pharmacology, 2,365.

NESTEL, P.J., HIRSCH, E.Z. & COUZENS, E.A. (1965) Theeffect of chlorophenoxyisobutyric acid and ethenyl estra-diol on cholesterol turnover. Journal of Clinical Investiga-tion, 44, 891.

OLIVER, M.F. (1963) Further observations on the effects ofAtromid and of ethyl chlorophenoxyisobutyrate on serumlipid levels. Journal of Atherosclerosis Research, 3, 427.

OLIVER, M.F. (1967a) Control of hyperlipidaemia. In RecentAdvances in Pharmacology and Therapeutics (Ed. byJ. Fulton). Butterworth, London.

OLIVER, M.F. (1967b) The present status of clofibrate.Circulation, 36, 337.

PENTECOST, B.L. & AUSTEN, W.C. (1966) Beta adrenergicblockade in experimental myocardial infarction. AmericanHeart Journal, 72, 790.

PLATT, D.S. & THORP, J.M. (1966) Changes in the weight andcomposition of the liver of the rat, dog and monkey treatedwith ethyl chlorophenoxyisobutyrate. Biochemical Pharma-cology, 15, 915.

POWELL, C.E. & SLATER, I.H. (1958) Blocking of inhibitoryadrenergic receptors by a dichloro analogue of isopro-terenol. Journal of Pharmacology, 122, 480.

SOWTON, E. (1968) Beta-adrenergic blockade in cardiac in-farction. Progress in Cardiovas-cular Diseases, 10, 561.

STANNARD, M., SLOMAN, G. & SANGSTER. L. (1968) Thehaemodynamic effects of atropine combined with pro-pranolol in acute myocardial infarction. MedicalJournal ofAustralia, 55, 333.

THORP, J.M. (1963) An experimental approach to theproblem of disordered lipid metabolism. Journal ofAtherosclerosis Resea,ch, 3, 35.

THORP, J.M. & WARING, W.S. (1962) Modification of meta-bolism and distribution of lipids by ethyl chlorophenoxy-isobutyrate. Nature, 194, 948.

VAUGHAN WILLIAMS. E.M. (1966) Mode of action of fI recep-tor antagonists on cardiac muscle. American Journal ofCa, diology, 18, 399.

WESTERFELD, W.W., RICHERT, D.A. & RUEGAMER, W.R.(1968) The role of the thyroid hormone in the effect ofp-chlorophenoxyisobutyrate in rats. Bicchemical Pharma-cology, 17, 1003.

WILSON, A.G., BROOK, O.G., LLOYD, H.J. & ROBINSON, B.F.(1969) Mechanism of action of JI adrenergic receptorblocking agents in angina pectoris: comparison of actionof pI opranolol with dexpropranolol and practolol. BritishMedical Jourral, 4, 399.

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