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

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1 Regular Review A hitch-hiker's guide to the galaxy of adrenoceptors GORDON M LEES The characteristic effects of activity of the sympathetic nervous system result from the action of the catecholamines noradrenaline and adrenaline on specialised components of cells called adrenoceptors (less correctly adrenergic receptors). Virtually every tissue has a noradrenergic innervation and is exposed to circulating adrenaline and noradrenaline, which evoke a wide variety of responses (table ). TABLE -Responses mediated by adrenoceptors Cell, organ, or system Adrenoceptor affected type Response Heart rbeta1> beta2 ncreased automaticity J Beta, ncreased conduction velocity Beta, ncreased excitability LBeta, (?also alpha) ncreased force of contraction Blood vessels. (Alpha Constriction of arteries and veins Beta, Dilatation of coronary arteries Beta2 Dilatation of most arteries Lung f Alpha Bronchoconstriction Beta2 > beta1 Bronchodilatation Skeletal muscle.... Beta, ncreased force and duration of contraction of fastcontracting muscle; decreased force and duration of contraction of slowcontracting muscle (hence tremor) Smooth muscles: Uterine muscle Beta2 Relaxation Eye.Alpha Mydriasis ntestinal muscle Beta, Relaxation (Alpha Augmentation of release of Mast cells J mediators of anaphylaxis * Beta nhibition of release of mediators of anaphylaxis Platelets.. Alpha2, beta Aggregation promoted Metabolism: Gluconeogenesis.. Alpha Promoted (Alpha (liver) Promoted Glycogenolysis Beta1 (heart) Promoted. Beta2 (skeletal Promoted muscle) Lipolysis (white adipocytes).. Beta1 Promoted Calorigenesis (brown adipocytes).. Beta1 Promoted Hormone secretion: Glucagon.. Beta. Promoted nsulin f Beta. Alpha nhibited Promoted Parathyroid hormone.. Beta Promoted Renin.. Beta, Promoted Neurotransmitter release: Acetylcholine.. Alpha Facilitated (skeletal neuromuscular junction); inhibited (sympathetic ganglia and intestine leading to inhibition/ relaxation) Noradrenaline falpha2 nhibited Facilitated 1.Beta (?beta.) There are two main types of adrenoceptors-namely, alpha and beta-with quite different pharmacological properties, and an organ may have more than one type. Some responses 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 the permeability of excitable membranes to ions. These effects are produced by the catecholamines combining with the receptors on the external surface of the cell membrane. nteractions between neurotransmitters and receptors often cause a change in the concentrations of compounds termed second messengers within the cell, which themselves modify cellular responses by controlling the activities of important intracellular enzymes. Two second messengers have been identified: adenosine-3',5'-monophosphate and guanosine- 3',5'-monophosphate. Adrenoceptor-mediated alterations in the concentrations ofthese two compounds result from changes in the membrane-bound enzymes adenylate cyclase and guanylate cyclase, which convert adenosine triphosphate and guanosine triphosphate to the corresponding cyclic nucleotides. Catecholamine-induced increases in intracellular concentration of adenosine-3',5'-monophosphate are usually associated with stimulation of beta-adrenoceptors, whereas alpha-adrenoceptor responses may be associated with lowered concentrations of adenosine-3',5'-monophosphate and possibly increased amounts of guanosine-3',5'-monophosphate in the cell. These changes may result in opposite effects being produced. The activity of these enzymes may also be modulated physiologically by acetylcholine, thyroid hormones, and vasopressin. Studies of the action of drugs which act as adrenoceptor agonists have concentrated on these modes of action, but they may influence other cellular mechanisms, such as have recently been described in the pancreas.2 Secretion of amylase can be achieved by activation of nerves that release neither acetylcholine nor noradrenaline (non-cholinergic, non-noradrenergic). Contrary to expectation, in response to stimulation of non-cholinergic, non-noradrenergic nerves there is no membrane depolarisation or calcium efflux associated with secretion. These findings show that changes in other possible cellular events need to be excluded before any particular response is labelled as the physiological effect of any substance or 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 rapid metabolic disposal of noradrenaline released as neurotransmitter. ts activity is slowly reduced by several inactivation mechanisms occurring almost simultaneously (fig 1). Firstly, the noradrenaline simply diffuses away from the receptor site. Secondly, unmetabolised noradrenaline can re-enter the noradrenergic nerve terminals by a special process termed neuronal uptake or Uptake,. Noradrenaline 173

2 174 FG 1-Diagrammatic representation of events at noradrenergic neuroeffector junctions in sympathetically innervated tissues. Noradrenaline is released from dense-core vesicles contained in the varicosities of the nerve terminal by exocytosis initiated by the influx of calcium ions during each nerve-action potential. Once released, noradrenaline diffuses within the junction to reach alpha-adrenoceptors or beta-adrenoceptors, or both, present on the effector-cell membrane; depending on the frequency of discharge of the nerve and the width of the junction, released noradrenaline may activate alpha2-adrenoceptors to reduce further release. Facilitation of release of noradrenaline mediated by beta-adrenoceptors is probably due physiologically to the action of adrenaline"' (see text). The effect of noradrenaline is terminated mainly through the neuronal uptake mechanism (Uptake,) and to much less extents in most tissues by extraneuronal uptake (Uptake,) and further diffusion into interstitial fluid. (MAO= Monoamine oxidase. COMT = Catechol-O-methyltransferase.) not so removed from the synaptic cleft will either diffuse further 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 uptake process but with different properties; it is referred to as extraneuronal uptake or Uptake2. Noradrenaline may be -methylated by the enzyme catechol-o-methyltransferase, which is thought to be located very close to the extraneuronal uptake site. n most tissues extraneuronal uptake plays a relatively unimportant part compared with neuronal uptake in terminating the action of noradrenaline released from peripheral noradrenergic nerves. After it has re-entered the nerves, noradrenaline is either metabolised within the nerve terminal, mainly by monoamine oxidase, or stored in the dense-core vesicles for further release. Adrenaline and noradrenaline released into the circulation have slightly different fates in the body, but overall O-methylation (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 endogenously produced substances present in the extracellular phase of the neuroeffector junction; these substances may be either locally produced or humoral agents3-8 (see table ). Basic pharmacological considerations More accurate predictions of the type of response to drug action on adrenoceptors require the ability to identify different types of adrenoceptor. The pharmacological effect of a drug is believed to result from the occupancy of a receptor to which the drug binds, even temporarily. Noradrenaline and adrenaline have affinity for the specific sites (adrenoceptors) on the cell membrane with which they combine. The extent of the resulting cellular responses defines the efficacy of these catecholamines. Compounds possessing both affinity for and efficacy at receptors are termed agonists. Agonists which act at adrenoceptors and elicit responses similar to those to noradrenaline and adrenaline are directly acting sympathomimetics; indirectly acting sympathomimetics have their action by causing the release of noradrenaline from noradrenergic nerves. Drugs which have affinity for but not efficacy at adrenoceptors are termed adrenoceptor antagonists or adrenoceptor-blocking drugs. Weak agonists with sufficient affinity for adrenoceptors to act as antagonists form a third category; such drugs are termed partial agonists because they cannot evoke the maximum response of which the cell is capable and may prevent the action of noradrenaline and adrenaline. Classification The classification of adrenoceptors is based on two separate approaches.9 1 n the first method, which is well established, a series of agonists is used to elicit particular effects in different organs or cells and the rank order of potency is determined on the assumptions that the relative intensities of agonist action at any one type of adrenoceptor will be the same irrespective of the tissue in which it is present and of the nature of the cellular response evoked; each drug, in eliciting the chosen response, activates reversibly only one type of adrenoceptor and has no other actions; the ease of access to the adrenoceptors and the fate (metabolic or other) of any one drug in the series are the same in the tissues studied; and the mode of action of the drugs is the same.9 Though this approach alone may be used, results are generally considered more reliable when they come from experiments in which the various responses to agonists have been prevented or abolished by antagonist drugs. Subclassifications and terminologies Ahlquist' showed that there were at least two types of adrenoceptor, which he designated alpha and beta. Lands and his colleagues1' suggested that there may be two distinct subclasses of beta-receptor, which they designated beta, and beta2. More recently, two subclasses of alpha-adrenoceptors, alpha, and alpha2, have been proposed.'2-2 To the nonpharmacologist the designations alpha,, alpha2, beta,, and beta2 may seem complex, confusing, and maybe even unnecessary, since their potential clinical or therapeutic value may not be obvious. They are used simply as a convenient shorthand notion for explaining (in part) why certain chemically related drugs may show some effects to a greater degree than do others. n practice these qualitative and quantitative differences in action between drugs or drug groups can be exploited for therapeutic or other purposes. The well- TABLE i-endogenously produced substances altering output of noradrenaline from sympathetic postganglionic noradrenergic nerve terminals Facilitation of release Adrenaline (beta2) Angiotensin Prostaglandin Focs nhibition of release Acetylcholine* (muscarinic: sinoatrial node) Adenosine Dopamine Enkephalin/beta-endorphint Histamine (H2) Noradrenaline (alpha2) Prostaglandin E series *Released from neighbouring nerves in the sinoatrial node (of unproved physiological significance elsewhere). tnhibition at low frequencies only and not in all nerves.

3 BRTSH MEDCAL JOURNAL VOLUME 283 known cardioselectivity of action of practolol and the important relaxant effects on uterine muscle of ritodrine are examples of drugs which show a greater tissue selectivity of action within their respective drug groups (table, 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 has been helpful in forecasting certain effects and side effects of beta-adrenoceptor agonists. Few drugs, however, have a high degree of selectivity-so that beta2-receptor agonists such 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 An additional complication is the probable occurrence of both subclasses of beta-adrenoceptor in the same tissue and mediating the same response-as in the heart, for example nvestigation of the alpha-adrenoceptors concerned in the feedback inhibition of release of noradrenaline showed that the agonists and antagonists most effective at this receptor (alpha2) were not the same as those used to characterise the classical alpha-adrenoceptor (alpha,) located on the postjunctional membrane of most sympathetically innervated tissues. Unfortunately, the occurrence of these two pharmacologically distinct receptor types has resulted in the inappropriate introduction of such anatomical terms as prejunctional (presynaptic) and postjunctional adrenoceptors. These anatomical terms have given rise to confusion when considering three important phenomena: firstly, alphaadrenoceptor-mediated inhibition (such as in autonomic ganglia and at enteric cholinergic synapses) and facilitation (at skeletal neuromuscular junctions) of the release of acetylcholine; secondly, vasoconstrictor responses to sympathomimetic amines; and, thirdly, platelet aggregation. n the first case the typing is not yet established but may be alpha2. n the second the evidence suggests that alpha2-adrenoceptors are to be found on vascular smooth muscle and that these, like the more conventional alpha1-receptors, mediate vasoconstriction.' Finally, platelet aggregation can be activated via alpha2-adrenoceptors. Clearly, therefore, anatomical terms may be used to describe locations but must not be used to describe or define physiological events or types of drug action for which an entirely separate terminology is appropriate. Rather less is known about the characteristics and physiological role of beta-adrenoceptor facilitation of noradrenaline release, but it may operate during conditions of stress as a result of the presence of adrenaline rather than noradrenaline (see Future developments). Rauwoiscine Yohimbine, Corynanthine Atenolol Metoprotol o Oxprenoltol a o Phentolamine 11 (-) Propranolot Phenoxybenzamine.i,. e Proctolol * 1 Kn. j[txnhz Adrenaline.Ln o Noradrenal ine Methoxanine < --Methylnoradrenatine* Clondine Oxymetazoline Tramazoli ne Phenylephrne Labetolol soprenaaline ips Butoxamine pe Salbutamol Terbutaline :R itod rine FG 2-Schematic representation of range of actions of agonists and antagonists at adrenoceptors; some are used solely for purposes of defining subclass of receptor mediating an effect. Length of bar gives indication of occurrence or otherwise of effect at subclass of receptor and indication of chances of clinically important effect being produced. Alpha, (al) adrenaline > noradrenaline, phenylephrine > a-methylnoradrenaline > > isoprenaline. Alpha2 (a2) oxymetazoline > clonidine > a-methylnoradrenaline > noradrenaline > > isoprenaline. Beta, (.1) isoprenaline > noradrenaline > adrenaline > > salbutamol. Beta2 (32) 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, and non-innervated blood vessels (such as umbilical arteries) may be of value in determining the spectrum of pharmacological activity of agonists and antagonists at the different subclasses of adrenoceptor. New method of detection The second, more recent approach to characterising adrenoceptors and for studying events at these sites depends on the concept that the receptor site must be occupied TABLE -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-methylagonists 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, yohimbine antagonists phenoxybenzamine prazosin, WB 411 (irreversible) Beta-adrenoceptor Alprenolol, dihydro- Acebutolol, atenolol, Butoxamine, PS-339 antagoniists alprenolol, oxprenolol, metoprolol, practolol pindolol, (-)-propranolol, sotalol, timolol Radiolabelled alpha- 3H-Carazolol, 3H-Azapetine, 3H-Clonidine adrenoceptor 'H-dihydroergocryptine 3H-prazosin, 3H-WB 411 antagonists Radiolabelled beta- 3H-Alprenolol, adrenoceptor 'H-dihydroalprenolol, antagonists ' 61-hydroxybenzylpindolol, '25-cyanopindolol 18 JULY

4 176 by drug molecules for an action to be produced. f, therefore, the drug molecules could be radiolabelled the binding of the drug to particular portions of cell membranes or other components would permit deductions to be made about the nature of the binding site and the location of the receptors for that drug. f all binding of radiolabelled drug molecules could be assumed to represent drug-receptor interactions, interpretation would be greatly simplified; unfortunately non-specific binding of drug molecules to tissue constituents occurs, probably because the adrenoceptors are composed of the same kinds of element (principally protein) from which many parts of the cell membrane are formed. The risk is that labelled drug molecules will bind to macromolecules unrelated to those uniquely linked to the biochemical machinery responsible for producing the characteristic response of the cell. Considerable problems are caused by this non-specific binding The basic principles underlying binding studies are well established. The capacity of the tissue to bind labelled drug molecules non-specifically is very large indeed compared with the maximum possible number of adrenoceptor-binding sites, but the latter show a far higher affinity for appropriate agonists and antagonists than do the large-capacity binding sites of the rest of the tissue. By choosing an appropriate concentration of drug molecules the receptors can be saturated, whereas saturation of all the non-specific binding sites is virtually impossible. f the cell is exposed to a very high concentration of unlabelled drug molecules there will be binding to both adrenoceptors and the non-specific binding sites. f 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 in occupancy of the receptor site by radioligand in exchange for unlabelled drug molecules-given that the type of binding concerned is reversible. Measuring the amount of drug bound at different concentrations of the radiolabelled drug shows that the amount of radiolabelled drug bound soon reaches a maximum (see fig 3). Several kinds of experiments of this type are possible using radiolabelled agonists and antagonists (listed in table ). Though the concepts are reasonably straightforward, such experiments must be designed with care and interpreted with caution The end results of radioligand experiments and of classical.c E c E D *max */ ~~~~ *1~~~~~1 VmxK * m * i.exe. Bound t Drug concentration (mol/1) B max FG 3-Diagrammatic representation of results obtained from radioligandbinding study. Ordinate: amount of ligand bound (mol/mg protein). Abscissa: concentration of ligand used (mol/l). nset: Scatchard plot of data. Ordinate: ratio of fractions of ligand bound and free. Abscissa: amount of ligand bound. ntercept Bmax gives estimate of maximum density of binding sites; intercept on y axis gives Bma4.KD, whence KD (dissociation constant), which can also be derived from slope of regression line (-1 /KD). pharmacological drug-receptor interaction-type experiments are not identical. Both approaches can be used to measure the affinity for an agonist and for a reversible competitive antagonist and to identify irreversible inactivation by an antagonist. Radioligand-binding studies do not, however, show the relative efficacies of agonists but can provide an estimate of the density of adrenoceptors in a tissue, information which cannot be obtained from classical procedures.3 Recent advances Radioligand studies offer enormous potential for the discovery of the location, number, and life span of different types of adrenoceptors Future progress will depend on the development of drugs which show an even greater discrimination of binding in their interaction with different classes of adrenoceptors and of drugs which act on one type of adrenoceptor in one particular tissue or cell type in preference to other tissues or cells while retaining specificity of action as agonists or antagonists at a particular pharmacological receptor. Such drugs might also be of benefit in therapeutics. Recently, there have been exciting discoveries in connection with alterations in the affinity of receptor sites for agonists and of regulation of the numbers (without a change in affinity) of receptors in different endocrine states33 38 and during long-term administration of certain drugs.394 Surely it will not be long before an impressive list is available of human conditions in which more or fewer adrenoceptors are found to be associated with the disorder. For example, in thyrotoxicosis, a condition long associated with concomitant excess sympathetic drive, there may be increased numbers of beta-adrenoceptors in the heart,33 though not necessarily in other tissues. n hypothyroidism, the change in numbers of alpha-adrenoceptors and beta-adrenoceptors is reversed. Of great clinical interest would be a satisfactory explanation of the reduced sensitivity of airways muscle to beta-adrenoceptor agonists in chronic persistent asthma. Since there is a similarity between the sensitivities of and activities mediated by beta-adrenoceptors ofhuman lymphocytes and lung tissue,4 the numbers of beta-receptors on circulating lymphocytes might be expected to be reduced to account for the subsensitivity-but whether or not any abnormality does exist in numbers or affinities of adrenoceptors on lymphocytes remains uncertain.33 ncreased concentrations of circulating catecholamines42 and repeated administration of a betareceptor agonist reduce sensitivity4 to the drug and all drugs acting on the same type of beta-adrenoceptor: that is, a kind of tolerance (and cross-tolerance) develops, so that more and more drug has to be given to produce the same degree of bronchodilatation. This state, however, may not be produced simultaneously in all tissues.43 The factors which regulate ("up" or "down" regulation)44 the number of beta-adrenoceptors need to be determined; another unanswered question is whether a similar regulation exists for alpha-adrenoceptors in view of reports that chronic administration of alphareceptor agonists may change the sensitivity of tissues to such agents.45 Some elegant electrophysiological studies at cholinergic synapses have shown that activation of acetylcholine receptors by different drugs does not lead to precisely the same time course of changes in permeability of the membrane. Whether the same will be true also of membrane permeability changes evoked by different adrenoceptor agonists remains to be determined. Again, studies of drug action at cholinoceptors have shown that in certain conditions the receptors may be

5 present but agonists may not be able to bind with them in such a way as to elicit the characteristic response. Hence, interestingly, the presence of guanosine triphosphate can regulate the function of the adenylate cyclase system affected by beta-receptor and alpha2-receptor agonists36 37 (but not the antagonists, which have no efficacy). Future developments The full clinical implications of all these findings are hard to assess, but as more information is acquired about the distribution of different subclasses of adrenoceptors and of the factors which control their numbers and their sensitivity to drugs one result seems likely to be new therapeutic approaches. Already in the treatment of heart failure use is being made of the differences between the pharmacological properties of prazosin and other readily available alphareceptor-blocking drugs. Prazosin can be used to reduce the work of the heart46 by preventing alpha1-receptormediated arteriolar and venous constrictions but without causing an undue reflex tachycardia, possibly because it has no effect on the alpha2-receptor-mediated inhibition of the release of noradrenaline from cardiac sympathetic nerves. Since human blood vessels are endowed with both types of alpha-adrenoceptor, prazosin is unable to block all vasoconstriction induced by noradrenaline or adrenaline Variations in the proportion of these two classes of receptors on arteries and veins in different vascular beds offer the possibility of changing the cardiac output or its distribution. Similarly the altered haemodynamics associated with the use of beta2-agonists (such as salbutamol) may be used to good effect in the management of cardiogenic shock.47 n the treatment ofnasal congestion, one of the disadvantages of using sympathomimetic amines such as oxymetazoline and naphazoline is rebound congestion. A possible explanation of this phenomenon is that in high concentrations oxymetazoline and naphazoline may act on the alpha-adrenoceptors of the smooth muscle of the arterioles of the nasal mucosa to cause a vasoconstriction directly. As the concentration of the drug falls, however, their agonist action at prejunctional alpha2- adrenoceptors may become unmasked; and by inhibiting the release of noradrenaline they may permit a passive dilatation of vessels with resultant nasal congestion. The use of agents which stimulate only alpha1-receptors may therefore be advantageous. The mechanism by which beta-adrenoceptor-blocking drugs produce their antihypertensive effect is still not clear. One interesting suggestion48 49 is that these drugs may simply prevent beta2-receptor-mediated facilitation of release of noradrenaline in blood vessels. On this hypothesis in hypertension beta-receptor-mediated facilitation is unusually pronounced owing to the release of adrenaline as well as noradrenaline from the noradrenergic nerve terminals-possibly because of increased concentrations of catecholamines circulating in the blood, particularly adrenaline,5 which can enter noradrenergic nerves by the neuronal uptake mechanism and so become available for release. f this were the case, cardioselective beta-blocking drugs (betaladrenoceptor blockers) would be expected to be less effective as antihypertensive agents than the non-selective beta-blocking drugs. The failure of this expectation to be confirmed from clinical experience could be due to different mechanisms of action being responsible for the same overall effect. For information on the possible central mechanisms of action of antihypertensive drugs, see Gross51 and Szekeres Some interest has been shown in the positive inotropic actions of sympathomimetic amines mediated by alphaadrenoceptors, but the potential clinical value of this action is uncertain. Perhaps of more promise is the possibility that the inotropic effect of beta-receptor agonists in the heart may be produced independently of changes in rate of beating, conduction velocity, or excitability, which also appear to be mediated via beta1-receptors. Possibly clinical use may be made of the recent observation53 that secretions of the choroid plexus can be augmented by activation by adenylate cyclase activity through beta-adrenoceptors. Clinical applications are less obvious for the selective beta2-adrenoceptor antagonists, except to minimise beta2- receptor-mediated release of insulin,54 glucagon,54 or parathyroid hormone,55 or to reduce tremor in skeletal muscles. These are likely to be among the unwanted effects of treatment with beta2-receptor agonists for severe bronchospasm. Summary n view of the widespread ramifications of noradrenergic nerve terminals in many tissues and the far greater number of postganglionic noradrenergic neurones with which any one preganglionic nerve synapses sympathetic nerve activity might be expected to be associated with equally widespread effects-or, at least, more of the tissue might be expected to be influenced by the neurotransmitter than if the same number of parasympathetic postganglionic cholinergic neurones had been activated. Similarly, the complex biochemical changes so often associated with activation of adrenoceptors would be expected to produce changes in the cell function which would outlast the usual transient changes in membrane permeability associated with activation of cholinoceptors. Furthermore, the effects of adrenoceptor activation by noradrenaline acting as neurotransmitter can be reinforced by the action of circulating adrenaline and noradrenaline released from the adrenal medullae. On the other hand, several mechanisms operate locally to control the amount of noradrenaline released during repetitive activity at different rates of discharge of postganglionic sympathetic nerves. 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 of available adrenoceptors mediating the responses observed. t has been known for many years that glucocorticoids need to be present for the full action of the catecholamines, but how these steroids play their permissive part is still to be resolved. Much of our knowledge of the pharmacology of adrenoceptors and of noradrenergic neurotransmission comes from investigations of sympathetically innervated tissues-because the junctions are more accessible for study than in the central nervous system. The mechanisms may not necessarily be the same within the central nervous system, where, for example, dopamine, noradrenaline, and adrenaline each act as neurotransmitter substances in different regions. The hope is that the information obtained from studies in the peripheral nervous system will be of value in advancing our understanding of a wide variety of disorders of the central nervous system and in unravelling physiological control mechanisms, such as those which operate to regulate arterial blood pressure. Senior lecturer in pharmacology, University of Aberdeen GORDON M LEES

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