BRITISH MEDICAL JOURNAL VOLUME 283 18 JULY 1981

Regular Review

A hitch-hiker's guide to the galaxy of adrenoceptors

GORDON M LEES

The characteristic effects of activity of the sympatheticnervous system result from the action of the catecholaminesnoradrenaline and adrenaline on specialised components ofcells called adrenoceptors (less correctly adrenergic receptors).Virtually every tissue has a noradrenergic innervation and isexposed to circulating adrenaline and noradrenaline, whichevoke a wide variety of responses (table I).

TABLE I-Responses mediated by adrenoceptors

Cell, organ, or system Adrenoceptoraffected type Response

rBeta1> beta2 Increased automaticityHeart J Beta, Increased conduction velocity

Beta, Increased excitabilityLBeta, ( ?also alpha) Increased force of contraction(Alpha Constriction of arteries and

Blood vessels . veinsBo Beta, Dilatation of coronary arteriesBeta2 Dilatation of most arteries

Lung fAlpha BronchoconstrictionBeta2> beta1 BronchodilatationSkeletal muscle .. .. Beta, Increased force and duration

of contraction of fast-contracting muscle;decreased force and durationof contraction of slow-contracting muscle (hencetremor)

Smooth muscles:Uterine muscle Beta2 RelaxationEye .Alpha MydriasisIntestinal muscle Beta, Relaxation

(Alpha Augmentation of release ofMast cells J mediators of anaphylaxis* Beta Inhibition of release of

mediators of anaphylaxisPlatelets .. Alpha2, beta Aggregation promotedMetabolism:

Gluconeogenesis .. Alpha Promoted(Alpha (liver) Promoted

Glycogenolysis Beta1 (heart) Promoted. Beta2 (skeletal Promoted

muscle)Lipolysis (white

adipocytes) .. Beta1 PromotedCalorigenesis (brown

adipocytes) .. Beta1 PromotedHormone secretion:Glucagon .. Beta. PromotedInsulin f Alpha Inhibited

Beta. PromotedParathyroid hormone .. Beta PromotedRenin .. Beta, Promoted

Neurotransmitter release:Acetylcholine .. Alpha Facilitated (skeletal

neuromuscular junction);inhibited (sympatheticganglia and intestineleading to inhibition/relaxation)

Noradrenaline fAlpha2 Inhibited1.Beta ( ?beta.) Facilitated

to the third type of endogenous catecholamine, dopamine,are mediated by another type of receptor.'The complex actions of the catecholamines include alterng

the activity of enzymes, metabolic pathways, and thepermeability of excitable membranes to ions. These effectsare produced by the catecholamines combining with thereceptors on the external surface of the cell membrane.Interactions between neurotransmitters and receptors oftencause a change in the concentrations of compounds termedsecond messengers within the cell, which themselves modifycellular responses by controlling the activities of importantintracellular enzymes. Two second messengers have beenidentified: adenosine-3',5'-monophosphate and guanosine-3',5'-monophosphate. Adrenoceptor-mediated alterations inthe concentrations ofthese two compounds result from changesin the membrane-bound enzymes adenylate cyclase and guany-late cyclase, which convert adenosine triphosphate and guano-sine triphosphate to the corresponding cyclic nucleotides.Catecholamine-induced increases in intracellular concentrationof adenosine-3',5'-monophosphate are usually associated withstimulation of beta-adrenoceptors, whereas alpha-adreno-ceptor responses may be associated with lowered concentrationsof adenosine-3',5'-monophosphate and possibly increasedamounts of guanosine-3',5'-monophosphate in the cell. Thesechanges may result in opposite effects being produced. Theactivity of these enzymes may also be modulated physiologic-ally by acetylcholine, thyroid hormones, and vasopressin.

Studies of the action of drugs which act as adrenoceptoragonists have concentrated on these modes of action, butthey may influence other cellular mechanisms, such as haverecently been described in the pancreas.2 Secretion of amylasecan be achieved by activation of nerves that release neitheracetylcholine nor noradrenaline (non-cholinergic, non-nor-adrenergic). Contrary to expectation, in response to stimulationof non-cholinergic, non-noradrenergic nerves there is nomembrane depolarisation or calcium efflux associated withsecretion. These findings show that changes in other possiblecellular events need to be excluded before any particularresponse is labelled as the physiological effect of any substanceor claiming that a drug is without effect in a tissue or cell type.Once released, catecholamines have a complex fate (compared

with that, say, of acetylcholine). For example, there is no rapidmetabolic disposal of noradrenaline released as neuro-transmitter. Its activity is slowly reduced by several inactiva-tion mechanisms occurring almost simultaneously (fig 1).Firstly, the noradrenaline simply diffuses away from thereceptor site. Secondly, unmetabolised noradrenaline canre-enter the noradrenergic nerve terminals by a specialprocess termed neuronal uptake or Uptake,. Noradrenaline

There are two main types of adrenoceptors-namely, alphaand beta-with quite different pharmacological properties,and an organ may have more than one type. Some responses

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FIG 1-Diagrammatic representation of events at noradrenergic neuroeffectorjunctions in sympathetically innervated tissues.

Noradrenaline is released from dense-core vesicles contained in the varicositiesof the nerve terminal by exocytosis initiated by the influx of calcium ions duringeach nerve-action potential. Once released, noradrenaline diffuses within thejunction to reach alpha-adrenoceptors or beta-adrenoceptors, or both, present on theeffector-cell membrane; depending on the frequency of discharge of the nerve andthe width of the junction, released noradrenaline may activate alpha2-adrenoceptorsto reduce further release. Facilitation of release of noradrenaline mediated bybeta-adrenoceptors is probably due physiologically to the action of adrenaline"'(see text). The effect of noradrenaline is terminated mainly through the neuronaluptake mechanism (Uptake,) and to much less extents in most tissues by extra-neuronal uptake (Uptake,) and further diffusion into interstitial fluid. (MAO=Monoamine oxidase. COMT = Catechol-O-methyltransferase.)

not so removed from the synaptic cleft will either diffusefurther away, perhaps even entering the venous blood, or

combine with other portions of the effector-cell membrane.One of these parts has the characteristics of another uptakeprocess but with different properties; it is referred to as

extraneuronal uptake or Uptake2. Noradrenaline may be0-methylated by the enzyme catechol-O-methyltransferase,which is thought to be located very close to the extraneuronaluptake site. In most tissues extraneuronal uptake plays a

relatively unimportant part compared with neuronal uptakein terminating the action of noradrenaline released fromperipheral noradrenergic nerves.

After it has re-entered the nerves, noradrenaline is eithermetabolised within the nerve terminal, mainly by monoamineoxidase, or stored in the dense-core vesicles for further release.Adrenaline and noradrenaline released into the circulationhave slightly different fates in the body, but overall O-methyla-tion (mainly in the liver and kidneys) is quantitatively more

important than deamination.The amount of noradrenaline released with each nerve

impulse may be facilitated or depressed by endogenouslyproduced substances present in the extracellular phase of theneuroeffector junction; these substances may be either locallyproduced or humoral agents3-8 (see table II).

Basic pharmacological considerations

More accurate predictions of the type of response to drugaction on adrenoceptors require the ability to identify dif-ferent types of adrenoceptor. The pharmacological effect ofa drug is believed to result from the occupancy of a receptorto which the drug binds, even temporarily. Noradrenalineand adrenaline have affinity for the specific sites (adreno-ceptors) on the cell membrane with which they combine.The extent of the resulting cellular responses defines theefficacy of these catecholamines. Compounds possessing both

BRITISH MEDICAL JOURNAL VOLUME 283 18 JULY 1981

affinity for and efficacy at receptors are termed agonists.Agonists which act at adrenoceptors and elicit responsessimilar to those to noradrenaline and adrenaline are directlyacting sympathomimetics; indirectly acting sympathomimeticshave their action by causing the release of noradrenaline fromnoradrenergic nerves. Drugs which have affinity for but notefficacy at adrenoceptors are termed adrenoceptor antagonistsor adrenoceptor-blocking drugs. Weak agonists with sufficientaffinity for adrenoceptors to act as antagonists form a thirdcategory; such drugs are termed partial agonists becausethey cannot evoke the maximum response of which the cellis capable and may prevent the action of noradrenaline andadrenaline.

ClassificationThe classification of adrenoceptors is based on two separate

approaches.9 10 In the first method, which is well established,a series of agonists is used to elicit particular effects in dif-ferent organs or cells and the rank order of potency is deter-mined on the assumptions that the relative intensities ofagonist action at any one type of adrenoceptor will be the sameirrespective ofthe tissue in which it is present and of the natureof the cellular response evoked; each drug, in eliciting thechosen response, activates reversibly only one type of adreno-ceptor and has no other actions; the ease ofaccess to the adreno-ceptors and the fate (metabolic or other) of any one drug in theseries are the same in the tissues studied; and the mode ofaction of the drugs is the same.9 Though this approach alonemay be used, results are generally considered more reliablewhen they come from experiments in which the various respon-ses to agonists have been prevented or abolished by antagonistdrugs.

Subclassifications and terminologiesAhlquist'0 showed that there were at least two types of

adrenoceptor, which he designated alpha and beta. Landsand his colleagues1' suggested that there may be two distinctsubclasses of beta-receptor, which they designated beta, andbeta2. More recently, two subclasses of alpha-adrenoceptors,alpha, and alpha2, have been proposed.'2-20 To the non-pharmacologist the designations alpha,, alpha2, beta,, andbeta2 may seem complex, confusing, and maybe even un-necessary, since their potential clinical or therapeutic valuemay not be obvious. They are used simply as a convenientshorthand notion for explaining (in part) why certain chemicallyrelated drugs may show some effects to a greater degreethan do others. In practice these qualitative and quantitativedifferences in action between drugs or drug groups canbe exploited for therapeutic or other purposes. The well-

TABLE iI-Endogenously produced substances altering output of noradrenalinefrom sympathetic postganglionic noradrenergic nerve terminals

Facilitation of release Inhibition of release

Adrenaline (beta2) Acetylcholine* (muscarinic: sinoatrial node)Angiotensin II AdenosineProstaglandin Focs Dopamine

Enkephalin/beta-endorphintHistamine (H2)Noradrenaline (alpha2)Prostaglandin E series

*Released from neighbouring nerves in the sinoatrial node (of unproved physiologicalsignificance elsewhere).tInhibition at low frequencies only and not in all nerves.

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known cardioselectivity of action of practolol and the im-portant relaxant effects on uterine muscle of ritodrine are

examples of drugs which show a greater tissue selectivity ofaction within their respective drug groups (table III, fig 2).Though from a purely pharmacological viewpoint the

evidence for subclasses of beta-adrenoceptors is not complete,in clinical practice the subdivision of beta-adrenoceptors hasbeen helpful in forecasting certain effects and side effects ofbeta-adrenoceptor agonists. Few drugs, however, have a

high degree of selectivity-so that beta2-receptor agonistssuch as salbutamol may be expected to affect the heart, and,contrariwise, beta,-receptor antagonists may precipitate or

worsen an attack of bronchial asthma for several reasons.21 22An additional complication is the probable occurrence of bothsubclasses of beta-adrenoceptor in the same tissue and media-ting the same response-as in the heart, for example.23 24

Investigation of the alpha-adrenoceptors concerned in thefeedback inhibition of release of noradrenaline showed thatthe agonists and antagonists most effective at this receptor(alpha2) were not the same as those used to characterise theclassical alpha-adrenoceptor (alpha,) located on the post-junctional membrane of most sympathetically innervatedtissues. Unfortunately, the occurrence of these two pharma-cologically distinct receptor types has resulted in the in-appropriate introduction of such anatomical terms as

prejunctional (presynaptic) and postjunctional adrenoceptors.These anatomical terms have given rise to confusion whenconsidering three important phenomena: firstly, alpha-adrenoceptor-mediated inhibition (such as in autonomicganglia and at enteric cholinergic synapses) and facilitation(at skeletal neuromuscular junctions) of the release of acetyl-choline; secondly, vasoconstrictor responses to sympatho-mimetic amines; and, thirdly, platelet aggregation. In thefirst case the typing is not yet established but may be alpha2.In the second the evidence suggests that alpha2-adrenoceptorsare to be found on vascular smooth muscle and that these,like the more conventional alpha1-receptors, mediate vaso-

constriction.'6 25-28 Finally, platelet aggregation can be activatedvia alpha2-adrenoceptors. Clearly, therefore, anatomical termsmay be used to describe locations but must not be used todescribe or define physiological events or types of drug actionfor which an entirely separate terminology is appropriate.Rather less is known about the characteristics and physiologicalrole of beta-adrenoceptor facilitation of noradrenaline release,but it may operate during conditions of stress as a result ofthe presence of adrenaline rather than noradrenaline (seeFuture developments).

Rauwoiscine Corynanthine

Yohimbine I,I I

o

a o Phentolamine 11eIPhenoxybenzamine.i,.

Labetolol

iIPS -3391Butoxaminepe

AtenololMetoprotol

Oxprenoltol(-) Propranolot

Proctolol

*0 1 IIIIIKn. j[TXnhZAdrenaline

Noradrenal ine

Methoxanine

.Ln Phenylephrneo I

< --Methylnoradrenatine*

Clondine

OxymetazolineTramazoli ne

Isoprenaaline

SalbutamolITerbutaline

:R itod rine

I

FIG 2-Schematic representation of range of actions of agonists andantagonists at adrenoceptors; some are used solely for purposes of definingsubclass of receptor mediating an effect. Length of bar gives indication ofoccurrence or otherwise of effect at subclass of receptor and indicationof chances of clinically important effect being produced. Alpha, (al)adrenaline > noradrenaline, phenylephrine > a-methylnoradrenaline > >isoprenaline. Alpha2 (a2) oxymetazoline > clonidine > a-methylnoradrena-line > noradrenaline > > isoprenaline. Beta, (.1) isoprenaline > noradrena-line > adrenaline > > salbutamol. Beta2 (032) salbutamol > isoprenaline >adrenaline > > noradrenaline.* Formed endogenously during treatment with a-methyldopa.

The interpretation of experiments on blood vessels with a

noradrenergic innervation is far from straightforward, andnon-innervated blood vessels (such as umbilical arteries) maybe of value in determining the spectrum of pharmacologicalactivity of agonists and antagonists at the different subclassesof adrenoceptor.

New method of detection

The second, more recent approach to characterisingadrenoceptors and for studying events at these sites dependson the concept that the receptor site must be occupied

TABLE III-List of commonly used agonists and antagonists at adrenoceptors, with radiolabelled derivatives used in binding studies

Non-selective action Alpha, Alpha2 Beta1 Beta,

Alpha-adrenoceptor Adrenaline noradrenaline, Methoxamine Clonidine, a-methyl-agonists phenylephrine noradrenaline,

naphazoline,oxymetazoline

Beta-adrenoceptor Adrenaline, isoprenaline Noradrenaline (?) Carbuterol, fenoterol,agonists isoetharine, orciprenaline,

rimiterol, ritodrine,salbutamol, salmefamol,terbutaline

Alpha-adrenoceptor Phentolamine, Corynanthine, indoramin, Rauwolscine, yohimbineantagonists phenoxybenzamine prazosin, WB 4101

(irreversible)Beta-adrenoceptor Alprenolol, dihydro- Acebutolol, atenolol, Butoxamine, IPS-339

antagoniists alprenolol, oxprenolol, metoprolol, practololpindolol, (-)-propranolol,sotalol, timolol

Radiolabelled alpha- 3H-Carazolol, 3H-Azapetine, 3H-Clonidineadrenoceptor 'H-dihydroergocryptine 3H-prazosin, 3H-WB 4101antagonists

Radiolabelled beta- 3H-Alprenolol,adrenoceptor 'H-dihydroalprenolol,antagonists ' 61-hydroxybenzyl-

pindolol,'25I-cyanopindolol

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by drug molecules for an action to be produced. If, therefore,the drug molecules could be radiolabelled the binding ofthe drug to particular portions of cell membranes or othercomponents would permit deductions to be made about thenature of the binding site and the location of the receptors

for that drug. If all binding of radiolabelled drug moleculescould be assumed to represent drug-receptor interactions,interpretation would be greatly simplified; unfortunatelynon-specific binding of drug molecules to tissue constituentsoccurs, probably because the adrenoceptors are composedof the same kinds of element (principally protein) fromwhich many parts of the cell membrane are formed. Therisk is that labelled drug molecules will bind to macro-

molecules unrelated to those uniquely linked to the biochemicalmachinery responsible for producing the characteristicresponse of the cell. Considerable problems are caused by thisnon-specific binding.29-34The basic principles underlying binding studies are well

established. The capacity of the tissue to bind labelled drugmolecules non-specifically is very large indeed compared withthe maximum possible number of adrenoceptor-binding sites,but the latter show a far higher affinity for appropriateagonists and antagonists than do the large-capacity bindingsites of the rest of the tissue. By choosing an appropriateconcentration of drug molecules the receptors can be saturated,whereas saturation of all the non-specific binding sites isvirtually impossible. If the cell is exposed to a very highconcentration of unlabelled drug molecules there will bebinding to both adrenoceptors and the non-specific bindingsites. If now, in the continued presence of unlabelled drug,the cell is exposed to a low concentration of radiolabelled drug,the high affinity of the adrenoceptors for the drug will result inoccupancy of the receptor site by radioligand in exchange forunlabelled drug molecules-given that the type of bindingconcerned is reversible. Measuring the amount of drug boundat different concentrations of the radiolabelled drug shows thatthe amount of radiolabelled drug bound soon reaches a

maximum (see fig 3). Several kinds of experiments of thistype are possible using radiolabelled agonists and antagonists(listed in table III). Though the concepts are reasonablystraightforward, such experiments must be designed withcare and interpreted with caution.30-32 34 3The end results of radioligand experiments and of classical

.c

0

E0

Ec

D

0

0

*max I

*1~~~~~1I~~~~*/ VmxK0

* m *i.exe

. Bound tB max

Drug concentration (mol/1)

FIG 3-Diagrammatic representation of results obtained from radioligand-binding study. Ordinate: amount of ligand bound (mol/mg protein).Abscissa: concentration of ligand used (mol/l). Inset: Scatchard plot of data.Ordinate: ratio of fractions of ligand bound and free. Abscissa: amount ofligand bound. Intercept Bmax gives estimate of maximum density of bindingsites; intercept on y axis gives Bma4.KD, whence KD (dissociation constant),which can also be derived from slope of regression line (-1 /KD).

BRITISH MEDICAL JOURNAL VOLUME 283 18 JULY 1981

pharmacological drug-receptor interaction-type experimentsare not identical. Both approaches can be used to measure theaffinity for an agonist and for a reversible competitiveantagonist and to identify irreversible inactivation by anantagonist. Radioligand-binding studies do not, however,show the relative efficacies of agonists but can provide anestimate ofthe density of adrenoceptors in a tissue, informationwhich cannot be obtained from classical procedures.3

Recent advances

Radioligand studies offer enormous potential for thediscovery of the location, number, and life span of differenttypes of adrenoceptors.33 34 36 37 Future progress will dependon the development of drugs which show an even greaterdiscrimination of binding in their interaction with differentclasses of adrenoceptors and of drugs which act on one typeof adrenoceptor in one particular tissue or cell type in pre-ference to other tissues or cells while retaining specificity ofaction as agonists or antagonists at a particular pharma-cological receptor. Such drugs might also be of benefit intherapeutics. Recently, there have been exciting discoveriesin connection with alterations in the affinity of receptor sitesfor agonists and of regulation of the numbers (without achange in affinity) of receptors in different endocrine states33 38and during long-term administration of certain drugs.3940Surely it will not be long before an impressive list is availableof human conditions in which more or fewer adrenoceptorsare found to be associated with the disorder. For example, inthyrotoxicosis, a condition long associated with concomitantexcess sympathetic drive, there may be increased numbers ofbeta-adrenoceptors in the heart,33 though not necessarily inother tissues. In hypothyroidism, the change in numbers ofalpha-adrenoceptors and beta-adrenoceptors is reversed.Of great clinical interest would be a satisfactory explanation

of the reduced sensitivity of airways muscle to beta-adreno-ceptor agonists in chronic persistent asthma. Since there is asimilarity between the sensitivities of and activities mediatedby beta-adrenoceptors ofhuman lymphocytes and lung tissue,4the numbers of beta-receptors on circulating lymphocytesmight be expected to be reduced to account for thesubsensitivity-but whether or not any abnormality doesexist in numbers or affinities of adrenoceptors on lymphocytesremains uncertain.33 Increased concentrations of circulatingcatecholamines42 and repeated administration of a beta-receptor agonist reduce sensitivity40 to the drug and alldrugs acting on the same type of beta-adrenoceptor: that is, akind of tolerance (and cross-tolerance) develops, so that moreand more drug has to be given to produce the same degree ofbronchodilatation. This state, however, may not be producedsimultaneously in all tissues.43 The factors which regulate("up" or "down" regulation)44 the number of beta-adreno-ceptors need to be determined; another unanswered questionis whether a similar regulation exists for alpha-adrenoceptorsin view of reports that chronic administration of alpha-receptor agonists may change the sensitivity of tissues to suchagents.45Some elegant electrophysiological studies at cholinergic

synapses have shown that activation of acetylcholine receptorsby different drugs does not lead to precisely the same timecourse of changes in permeability of the membrane. Whetherthe same will be true also of membrane permeability changesevoked by different adrenoceptor agonists remains to bedetermined. Again, studies of drug action at cholinoceptorshave shown that in certain conditions the receptors may be

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BRITISH MEDICAL JOURNAL VOLUME 283 18 JULY 1981

present but agonists may not be able to bind with them insuch a way as to elicit the characteristic response. Hence,interestingly, the presence of guanosine triphosphate canregulate the function of the adenylate cyclase system affectedby beta-receptor and alpha2-receptor agonists36 37 (but notthe antagonists, which have no efficacy).

Future developments

The full clinical implications of all these findings arehard to assess, but as more information is acquired aboutthe distribution of different subclasses of adrenoceptors andof the factors which control their numbers and their sensitivityto drugs one result seems likely to be new therapeutic ap-proaches. Already in the treatment of heart failure use isbeing made of the differences between the pharmacologicalproperties of prazosin and other readily available alpha-receptor-blocking drugs. Prazosin can be used to reducethe work of the heart46 by preventing alpha1-receptor-mediated arteriolar and venous constrictions but withoutcausing an undue reflex tachycardia, possibly because ithas no effect on the alpha2-receptor-mediated inhibition ofthe release of noradrenaline from cardiac sympathetic nerves.Since human blood vessels are endowed with both types ofalpha-adrenoceptor, prazosin is unable to block all vaso-constriction induced by noradrenaline or adrenaline.25 26Variations in the proportion of these two classes of receptorson arteries and veins in different vascular beds offer thepossibility of changing the cardiac output or its distribution.Similarly the altered haemodynamics associated with the useof beta2-agonists (such as salbutamol) may be used to goodeffect in the management of cardiogenic shock.47

In the treatment ofnasal congestion, one ofthe disadvantagesof using sympathomimetic amines such as oxymetazoline andnaphazoline is rebound congestion. A possible explanation ofthis phenomenon is that in high concentrations oxymetazolineand naphazoline may act on the alpha-adrenoceptors of thesmooth muscle of the arterioles of the nasal mucosa to cause avasoconstriction directly. As the concentration of the drugfalls, however, their agonist action at prejunctional alpha2-adrenoceptors may become unmasked; and by inhibiting therelease of noradrenaline they may permit a passive dilatationof vessels with resultant nasal congestion. The use of agentswhich stimulate only alpha1-receptors may therefore beadvantageous.The mechanism by which beta-adrenoceptor-blocking drugs

produce their antihypertensive effect is still not clear. Oneinteresting suggestion48 49 is that these drugs may simplyprevent beta2-receptor-mediated facilitation of release ofnoradrenaline in blood vessels. On this hypothesis in hyper-tension beta-receptor-mediated facilitation is unusually pro-nounced owing to the release of adrenaline as well as nor-adrenaline from the noradrenergic nerve terminals-possiblybecause of increased concentrations of catecholaminescirculating in the blood, particularly adrenaline,50 whichcan enter noradrenergic nerves by the neuronal uptakemechanism and so become available for release. If thiswere the case, cardioselective beta-blocking drugs (betal-adrenoceptor blockers) would be expected to be less effectiveas antihypertensive agents than the non-selective beta-blockingdrugs. The failure of this expectation to be confirmed fromclinical experience could be due to different mechanisms ofaction being responsible for the same overall effect. Forinformation on the possible central mechanisms of action ofantihypertensive drugs, see Gross51 and Szekeres.52

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Some interest has been shown in the positive inotropicactions of sympathomimetic amines mediated by alpha-adrenoceptors, but the potential clinical value of this action isuncertain. Perhaps of more promise is the possibility thatthe inotropic effect of beta-receptor agonists in the heart maybe produced independently of changes in rate of beating,conduction velocity, or excitability, which also appear to bemediated via beta1-receptors. Possibly clinical use may bemade of the recent observation53 that secretions of the choroidplexus can be augmented by activation by adenylate cyclaseactivity through beta-adrenoceptors.

Clinical applications are less obvious for the selectivebeta2-adrenoceptor antagonists, except to minimise beta2-receptor-mediated release of insulin,54 glucagon,54 or para-thyroid hormone,55 or to reduce tremor in skeletal muscles.These are likely to be among the unwanted effects of treatmentwith beta2-receptor agonists for severe bronchospasm.

Summary

In view of the widespread ramifications of noradrenergicnerve terminals in many tissues and the far greater numberof postganglionic noradrenergic neurones with which anyone preganglionic nerve synapses sympathetic nerve activitymight be expected to be associated with equally widespreadeffects-or, at least, more of the tissue might be expectedto be influenced by the neurotransmitter than if the samenumber of parasympathetic postganglionic cholinergicneurones had been activated. Similarly, the complex bio-chemical changes so often associated with activation ofadrenoceptors would be expected to produce changes in thecell function which would outlast the usual transient changesin membrane permeability associated with activation ofcholinoceptors. Furthermore, the effects of adrenoceptoractivation by noradrenaline acting as neurotransmitter can bereinforced by the action of circulating adrenaline and nor-adrenaline released from the adrenal medullae. On the otherhand, several mechanisms operate locally to control theamount of noradrenaline released during repetitive activity atdifferent rates of discharge of postganglionic sympatheticnerves.The intensity of action of the catecholamines (and of

exogenously administered drugs used to mimic their effects)can be influenced by several factors including the number ofavailable adrenoceptors mediating the responses observed. Ithas been known for many years that glucocorticoids need tobe present for the full action of the catecholamines, but howthese steroids play their permissive part is still to be resolved.Much of our knowledge of the pharmacology of adrenoceptorsand of noradrenergic neurotransmission comes from investiga-tions of sympathetically innervated tissues-because the junc-tions are more accessible for study than in the central nervoussystem. The mechanisms may not necessarily be the samewithin the central nervous system, where, for example,dopamine, noradrenaline, and adrenaline each act as neuro-transmitter substances in different regions. The hope is thatthe information obtained from studies in the peripheralnervous system will be of value in advancing our understandingof a wide variety of disorders of the central nervous systemand in unravelling physiological control mechanisms, such asthose which operate to regulate arterial blood pressure.

GORDON M LEESSenior lecturer in pharmacology,University of Aberdeen

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