Central nervous control of blood pressure in relation to antihypertensive drug treament

Pharmac. Ther. Vol. 13, pp. 321 356 © Pergamon Press Ltd 1981. Printed in Great Britain

0163 725881 070

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Specialist Subject Editor: AUSTIN DOYLE

CENTRAL NERVOUS CONTROL OF BLOOD IN RELATION TO ANTIHYPERTENSIVE TREATMENT

PRESSURE DRUG

P. I. KORNER and J. A. ANGUS Baker Medical Research Institute, Prahran, Victoria, Australia, 3181

1. INTRODUCTION The understanding of the operation of different CNS (Table 1) mechanisms in circulatory control needs knowledge of both the various sensory inputs (e.g. arterial baroreceptors) and the properties of the different effector organs. The latter are particularly important in hypertension since the hypertrophied muscle of hypertensive vessels and the heart 'amplify' neural activity and accentuate the responses of antihypertensive drugs. The first part of this paper briefly summarizes present knowledge of the different components of the cardiovascular control system from the viewpoint of overall operation in the intact organism. More detailed accounts of physiological aspects of CNS control are available in several reviews (Koizumi and Brooks, 1972; Korner, 1971, 1978, 1979, 1980; Chalmers, 1975; Kirchheim, 1976; Manning, 1977; Thoren, 1979; Brown, 1980; Dampney, 1981). The second part of the review discusses the cardiovascular role of central neurons which release catecholamines and serotonin from their endings during neural activity. These actions are relevant to the actions of the commonly used antihypertensive drugs since many of them modify the functions of these neurons. There is also brief discussion of the role of GABA and glutamate, the CNS effects of angiotensin II and of the opioid transmitters. TABLE 1. Table of Abbreviations ACTH ADH AII BPs0 CA CNS COHG CSF DA DHT DOPA GABA HP 5HT 5HTP i.c.v, ILN ISA i.v. MAP n NA NTS 6-OHDA PCPA Po2 SNA

adrenocorticotrophic hormone antidiuretic hormone angiotensin II median blood pressure catecholamine central nervous system carboxyhaemoglobin cerebrospinal fluid dopamine dihydroxytryptamine dihydroxyphenylalanine ?-aminobutyric acid heart period serotonin (5-hydroxytryptamine) 5-hydroxytryptophan intracerebroventricular intermediolateral nucleus intrinsic sympathomimetic activity intravenous mean arterial pressure nucleus noradrenaline nucleus tractus solitarius 6-hydroxydopamine parachlorophenylalanine oxygen pressure sympathetic nerve activity 321

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The last part of the paper considers briefly the mechanisms of actions of clonidine. guanfacine, a-methyl dopa and /~-adrenoceptor blocking drugs. Most of these have actions on several components of the circulatory control system. Drugs with actions predominantly outside the CNS (e.g. diuretics and vasodilators) pose special problems of cardiovascular control but are only briefly considered. 2. NORMAL OPERATION OF THE CARDIOVASCULAR CONTROL SYSTEM 2.1. COMPONENTS OF THE SYSTEM

In the intact organism an environmental disturbance or a drug elicits a circulatory response partly through its direct effects on the heart and blood vessels and partly through its reflex autonomic effects (Fig. 1). The direct circulatory effects produce changes in various intravascular pressures which are signalled to the CNS through the arterial baroreceptors of the carotid sinus and aortic arch and through cardiopulmonary baroreceptors, of which the atrial and ventricular receptors are probably the most important (Paintal, 1973; Kirchheim, 1976; Thoren, 1979; Brown, 1980). The disturbance may alter other bodily functions and change the activity of appropriate sensory receptors (e.g. thermal receptors, arterial chemoreceptors, lung inflation receptors, and many types of somatic and visceral receptors). The overall information is integrated by the CNS and gives rise to a characteristic pattern of autonomic neural activity, adrenal catecholamine secretion and sometimes the production of other hormones (e.g. angiotensin II, vasopressin). The afferents from the arterial baroreceptors travel in the 9th and 10th cranial nerves and enter the medulla oblongata. Their first synapse is situated in the nucleus of the tractus solitarius (NTS). This is a complex integrative site which also contains the primary central synapses of afferents from the cardiopulmonary baroreceptors, the arterial chemoreceptors and the lung inflation receptors which signal changes in respiratory minute volume and rate (Spyer, 1975; for other references see Korner, 1979). In addition, the NTS receive axons from several parts of the brain, some of which are capable of modulating the afferent activity, much as occurs in other sensory systems (Weiss and Crill, 1969). Other inputs from the periphery from numerous visceral and somatic afferents enter through the dorsal roots of the spinal cord. These afferents include the socalled sympathetic afferents from the heart and great vessels (Malliani, 1975; Thoren, 1979). They probably contribute to cardiovascular control particularly during large changes in blood pressure and in cardiac dimensions (Malliani, 1975; Thoren, 1979). The CNS pathways linking the inputs to the autonomic outputs are shown schematically in Fig. 2. From any one type of sensory input there are projections to many

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integrative sites, in some instances ranging from cortex to spinal cord but generally traversing numerous synapses. Thus from NTS neurons receiving baroreceptor projections axons project directly to four major sites:-~i) the spinal cord (Loewy and Burton, 1978); (ii) the parabrachial nucleus near the brachium conjunctivum of the pons (Saper and Loewy, 1980); (iii) the ambiguus complex of the rostral medulla; (iv) the hypothalamus (Loewy and McKellar, 1980; Dampney, 1981). From each of these there are numerous secondary and higher projections so that eventually arterial baroreceptor information becomes very widely dispersed, e.g. to several parts of the cortex, hypothalamus and to the limbic nuclei. The autonomic outflows are situated in preganglionic vagal motoneurons in the medulla (Geis and Wurster, 1980; Korner, 1979) and in the preganglionic sympathetic neurons. Each motoneuron pool contains several thousand neurons and is the site of convergence of axons from many parts of the brain. The sympathetic motoneurons lie in the intermedio-lateral nucleus (ILN) of the thoraco-lumbar regions of the spinal cord. The direct sources of afferent fibres come from (i) NTS; (ii) ventrolateral reticular and ventral raphe nuclei; (iii) NA neurons from the pons (Amendt et al., 1979; Loewy and McKellar, 1980; Dampney, 1981); (iv) from the hypothalamus (Smith, 1965, Saper et al., 1976; Blessing and Chalmers, 1979). They supply the fibres to the sympathetic ganglia, from which postganglionic fibres go to the heart and the sympathetic constrictors to the various regional beds. In addition the preganglionic fibres go directly to the adrenal medulla. There are also specialized outflows, including the cholinergic vasodilator fibres to skeletal muscle vessels (Zanchetti et al., 1976). The sacral ILN neurons send vasodilator fibres to the genital and pelvic organs. Thus the number of brain regions capable of influencing a particular autonomic motoneuron pool is as extensive as the number of regions receiving a particular type of sensory input. The pathways from a given region often involve several interneurons and there appear to be connections through parallel pathways from distinctive integrative sites. Not all pathways to a given motoneuron pool are believed to be active at any one time, but one or other becomes activated in response to specific physiological circumstances. For example, in the rabbit there is a sympathetically mediated tachycardia during mild arterial hypoxia (art Po2 > 35 mmHg), but an increasing degree of bradycardia due to increased vagal and decreased sympathetic activity as arterial Po2 falls

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below this critical level, which corresponds to the rabbit's maximum respiratory response (Korner, 1979). Whether or not there is tachycardia or bradycardia depends on the relative magnitude of the input from lung inflation receptors and that from the arterial chemoreceptors. In mild hypoxia the lung inflation receptor/chemoreceptor input ratio is relatively high; a lung inflation receptor-activated cortical 'centre" suppresses the activity of a chemoreceptor activated hypothalamic centre. The heart rate response of the intact animal then has the same characteristics as in pontine (decerebrate) rabbits, suggesting that it is mediated through a bulbo-spinal pathway (Fig. 3). Below arterial Po2 35 m m H g the magnitude of the lung inflation receptor input tends to remain fixed or even fall, whilst arterial chemoreceptor activity increases with further reduction in arterial Po2. This results in increasing bradycardia through a hypothalamic pathway (Fig. 3). Figure 3 illustrates what applies to virtually every type of activity, whether reflexly evoked or in response to central 'command', namely that suprapontine as well as bulbospinal mechanisms are involved. The idea that reflexes were integrated through the latter and that suprapontine regions subserved mainly special tasks such as thermoregulation or voluntary tasks, is no longer valid in the light of studies in conscious animals. Each disturbance has its distinctive pattern of vagal and sympathetic neural activity and adrenal catecholamine secretion, whether evoked by distinctive profiles of afferent activity (Fig. 4) or by central 'command' (Fig. 5). With some disturbances the sympathetic neural response pattern is non-uniform, and activity increases in some outflows and decreases in others (Fig. 4, arterial hypoxia). There is now considerable evidence against Cannon's view that the sympathetic nervous system is a system for uniform mass action to help the organism cope with emergencies (Koizumi and Brooks, 1972; Korner, 1979). For the production of some of these differentiated sympathetic neural effector patterns the integrity of forebrain and/or diencephalic mechanisms appears to be essential (J~inig, 1975; Korner, 1980). Characteristic autonomic patterns also occur in response to psychological stimuli and during voluntary activity such as exercise. One such response is the well known 'defence'

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reaction (Fig. 5) comprising tachycardia, increased activity of renal and splanchnic sympathetic constrictor nerves and increased activity of the cholinergic sympathetic vasodilator nerves (Zanchetti et al., 1975). The full pattern can be evoked by electrically stimulating a small localised area in the ventromedial hypothalamus, the 'defence' area. Smith and colleagues (1980) have recently described a region in the lateral hypothalamus of baboons which mediates tachycardia, hypertension, renal vasoconstriction and hindlimb vasodilatation after conditioning the monkeys to anticipate painful stimulus. After ablation of the critical region in the hypothalamus the conditioning stimulus no longer elicits a response but there are no alterations at all in the response patterns evoked by exercise or by feeding. These seem to be central 'command' mechanisms which allow specific stimulus to execute a characteristic 'program' of autonomic activity. 2.2. MULTIPLE AFFERENT STIMULI: SUMMATION AND NoN-LINEAR INTERACTIONS A given circulatory disturbance rarely alters the activity of a single group of sensory receptors in the intact organism, and more commonly the activity is simultaneously altered in several afferents. The evoked autonomic response can then be either (i) the simple sum of individual reflex responses that would be elicited if each receptor group was stimulated separately under classic 'open loop' conditions (Fig. 1); or (ii) a non-linear response which is not predictable from the individual open-loop reflex effects; or (iii) a combination of (i) and (ii). Suppose that two receptors A and B are stimulated simultaneously and that under open-loop conditions a standard stimulus of A evokes a response of magnitude A', whilst stimulation of B elicited the response B'. If both are stimulated together (A + B) will elicit responses (A' + B') in accordance with the summation model of reflex activity. Under other condition stimulation of (A + B) will evoke the non-linear response

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FIG. 6. Schemata show different mechanisms whereby mean arterial pressure heart period curve can become reset during a disturbance (heavy curve) from its normal position (light curve). A: when reflex heart rate neurons are activated through pathways that are independent of those receiving baroreceptor projections, only mean level of heart period is altered but none of the arterial pressure-related parameters change (i.e. heart period range, gain, median blood pressure, and threshold). B: disturbance has evoked arterial pressure-independent effects with equal shifts in the two plateau levels; there have also been some effects of motoneuron pool receiving baroreceptor projections that have resulted in lowering of median blood pressure and threshold. C: effect of disturbance is entirely on parts of pool receiving projections from baroreceptors and every parameter of the curve has been altered. Shift in upper plateau level is entirely due to increase in heart period range (From Korner et al.. 1973, by permission of A m e r . H e a r t Association).

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FIG. 7. Curves showing relationship between mean arterial pressure and renal sympatheticnerve activity (SNA) in anesthetized, artificially ventilated rabbits during ventilation with room air (closed circles, thin line) and during severe arterial hypoxia (triangles, thick line). 100 per cent = renal SNA at arterial pressure 60 mmHg during ventilation with room air. Left: resultsfrom 6 rabbits with intact CNS; Right:--results from 6 other decerebrate rabbits (Based on data from Iriki and Kroner, 1979). (A' + B' + A'B'), where the last term is the interaction term. A large interaction term means that the autonomic response produced by a change in one of the inputs is markedly influenced by the level of activity in the other input. Different disturbances after the characteristics of arterial baroreceptor-heart rate reflex function curves in ways that allow one to distinguish whether the effects of multiple afferents are in accord with the summation or the interaction model (Fig. 6); (Korner et al., 1973). Under control conditions the relationship between mean arterial pressure (MAP) and heart period (HP, pulse interval) is described by a Gaussian distribution function curve which can be characterised by the following parameters :--(i) the H P Range (i.e. AHP between the plateau levels); (ii) the gain or sensitivity and (iii) the median blood pressure (BPso, i.e. MAP at half the H P Range). When during a disturbance another input exerts effects that summate with those evoked by the baroreceptors the change in the function curve consists of an equal change in both the plateau levels of the curve but not in the arterial pressure-related curve parameters (Fig. 6A). This suggests that the other input engages a group of heart rate neurons distinctive from those engaged by the baroreceptors. This type of change occurs during alterations in respiratory minute volume in the rabbit when the shift in the curve is reflexly mediated through changes in activity in the lung inflation receptors (Korner et al., 1973). When there is interaction within the CNS between the projections of the inputs involved in the disturbance and those from the arterial baroreceptors, for example, by projections on to a common integrative site, there may be considerable changes in the arterial pressure-related curve parameters (Fig. 6C). Changes in arterial baroreceptorheart rate reflex curve parameters occur in the rabbit during arterial hypoxia due to simultaneous changes in arterial chemoreceptor and cardiopulmonary baroreceptor activity (Korner et al., 1973; Heistad et al., 1974; Wennergen et al., 1976). There are also changes in renal sympathetic baroreceptor reflex properties, due to interactions involving the arterial baroreceptors and chemoreceptors (Iriki et al., 1977; Iriki and Korner, 1979) (Fig. 7). These changes are abolished by decerebration, suggesting that the interactions involve suprapontine mechanisms.

2.3. HOMEOSTATICSIGNIFICANCEOF CNS 'RESETTING'OF ARTERIAL BAROREFLEX PROPERTIES Scher and Young (1969) have pointed out that the gain of the arterial baroreceptor reflex as studied in the isolated carotid sinus preparation varies continuously and is maximal close to the animal's resting blood pressure (Fig. 8) (Korner, 1980). This has important implications for the effectiveness of the arterial baroreceptor reflex when the arterial baroreceptors signal changes corresponding to large and small circulatory perturbations. The direct effects on the cardiovascular system of a circulatory disturbance

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can be assessed under 'open loop' conditions, e.g. after autonomic blockade (Korner and Uther, 1969). The body's capacity to compensate is then assessed from a comparison of the 'open loop' responses with the 'closed loop' responses of the intact animal (Fig. 9). With the arterial baroreceptor reflex gain as shown in Fig. 8, only small perturbations will be compensated effectively through this reflex. As the perturbation becomes large, compensation will become inadequate because the gain or sensitivity of the reflex rapidly falls off (Figs 8, 9 [top panel]). INPUTS

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A number of non-linear CNS interactions involving the arterial baroreceptors and a number of other inputs increase the apparent gain of the arterial baroreceptor reflex and thereby extend the magnitude of the direct circulatory perturbations that can be compensated adequately. These changes in compensating capacity are illustrated schematically in the responses of three different types of tissue hypoxia in the conscious rabbit in which reflex 'drive' was provided by different combinations of afferents (Fig. 9). They were :--(i) carbon monoxide hypoxia in which reflex 'drive' comes almost entirely through the arterial baroreceptors; (ii) arterial hypoxia where it involves arterial chemoreceptors, arterial and cardiopulmonary baroreceptors and lung inflation receptors; (iii) hemorrhage where the major afferents are the arterial and cardiopulmonary baroreceptors (for references see Korner, 1978, 1980); (note distinctive response patterns with each afferent input profile in Fig. 4). The severity of each type of tissue hypoxia was such that under 'open loop' conditions it produced closely similar falls in blood pressure and the same degree of peripheral vasodilatation in all major vascular beds (Korner et al., 1967). Figure 10 shows that during carbon monoxide hypoxia intact rabbits compensated for only about 50 per cent of the direct effects of the disturbance. By contrast, in arterial hypoxia where the open-loop effects on blood pressure were virtually identical, there was an initial overcorrection of the direct circulatory effects and even after 45 rain of hypoxia this combination of afferents provided sufficient 'drive' to correct for more than 90 per cent of the direct circulatory changes. During hemorrhage consisting of removal of 26 per cent of the animal's blood volume the apparent gain of the baroreflex also becomes enhanced. For example, the same fall in blood pressure as in carbon monoxide hypoxia is associated with considerably more pronounced renal vasoconstriction after hemorrhage (Mancia et al., 1975; Korner, 1978). 2.4. PERIPHERAL LOCAL AND AUTONOMIC INTERRELATIONSHIPS The cardiac and vascular smooth muscle of the regional resistance vessels integrate the direct local effects of a disturbance and the evoked neural and adrenal effects (c.f. Fig. 1). Postsynaptic receptors on cardiac and different vascular smooth muscle membranes respond to (i) acetyl choline released from the vagus and from sympathetic cholinergic vasodilator nerves in the skeletal muscle vessels which mediate their effects through specific muscarinic receptors; (ii) noradrenaline (NA) released from sympathetic nerves; (iii) circulating NA and adrenaline released from the adrenal medulla.

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All vascular beds are innervated by sympathetic constrictor nerves, with considerable differences in innervation density (Gillespie and Rae, 1972). The sympathetic constrictor nerves to arteries are virtually confined to the border between adventitia and media, and distensibility studies suggest that during nerve stimulation it is the outer ring of the smooth muscle that is predominantly excited. By contrast, maximum tension changes during stretch affect the inner coat to a greater degree than the outer coat, thus providing some basis for the spatial separation of the different stimuli (for references see Koroer, 1974). The effects of sympathetic nerve stimulation on the precapillary resistance vessels are predominantly on the ~-adrenoceptors of the vascular smooth muscle suggesting that these are again spatially separated from/Ladrenoceptors. Normally there is minimal, if any, stimulation, of vascular /3-adrenoceptors during sympathetic nerve stimulation (Glick et al., 1967; Korner et al., 1967). Different regional beds appear to differ in relative magnitude of the populations of ~- to fl-adrenoceptors. For example, skin vessels have a higher proportion of c~-receptors than skeletal muscle vessels. With prolonged disturbances lasting minutes and hours rather than seconds the adrenal catecholamines are important modulators of the effects on vascular resistance mediated through the sympathetic nerves (Korner and Uther, 1975). Thus in the rabbit during 45 rain of severe arterial hypoxia they double the rise in vascular resistance over that mediated through sympathetic nerves, presumably by engaging more ~-receptors in that bed. In the skeletal muscle bed they act on fl-adrenoceptors to produce vasodilatation which completely masks the ~-adrenoceptor mediated neural constrictor effects (cf Fig. 4) (Korner et al., 1967). NA released from sympathetic nerve terminals has been considered to stimulate not only postsynaptic receptors but also presynaptic receptors (Rand et al.. 1975; Langer, 1977; Langer et al., 1980; Starke, 1977). It has been postulated that stimulation of presynaptic ~-adrenoceptors provide an inhibitory feedback which limits further transmitter release. Other types of presynaptic receptors have also been described, e.g. fl-receptors, dopamine (DA) receptors, serotonin (5HT) receptors (Rand et al., 1980). There is no doubt that presynaptic receptors are important in relation to the action of clonidine and possibly other antihypertensive drugs. The question considered here is the extent to which presynaptic ~-receptors are important physioloyical modulators of transmitter release i.e. during release of NA corresponding to resting levels of sympathetic activity and during moderate increase in the latter. Evidence that NA acts through a presynaptic auto-inhibitory feedback loop was suggested in experiments in the guinea pig right atrium showing that phenoxybenzamine and phentolamine potentiated the response to sympathetic nerve stimulation and increased the overflow of radioactively labeled noradrenaline (Rand et al., 1975; Langer,

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Blood pressure control and antihypertensivedrugs

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1977). The greatest effect after ~-adrenoceptor blockade on overflow of labeled transmitter has been found with stimuli of 4-5 Hz applied for 30 sec. These stimuli produce maximum effects on heart rate and contractile force and the effects on transmitter release would only apply to high levels of sympathetic activity. Two recent studies have not been able to establish such an effect either on transmitter release or on the effector response under conditions when presynaptic modulation might have been expected (Kalsner and Chan, 1979; Angus and Korner, 1980). In the guinea pig right atrium the tachycardia response to sympathetic stimulation, extending from low levels to about 80 per cent of the maximum response, was completely unaltered by ~-adrenoceptor blockade with phentolamine and yohimbine (Fig. 11). In our opinion based on these studies there is at present no compelling evidence that over a range of nerve stimuli extending from resting to about 80 per cent of maximum response there is feedback inhibition of further transmitter release through presynaptic a-receptors. The magnitude of neural sympathetic responses evoked through the CNS would thus appear to be almost entirely due to changes in activity of the preganglionic sympathetic nerves, and additional modulation through presynaptic mechanisms of the nerve endings is of little, if any, consequence under physiological circumstances. However, presynaptic mechanisms are important in the antihypertensive action of clonidine (see Section 4.1). 2.5. AUTONOMIC EFFECTS AND INTRINSIC CIRCULATORY CHANGES IN HYPERTENSION It is still an open question as to what extent autonomic activity is abnormal in essential or secondary hypertension. However, there is no doubt that the hypertrophy of the vascular smooth muscle and of the heart in hypertension contributes to the greater rises in blood pressure and vascular resistance during various constrictor and inotropic stimuli compared with their effects in the normotensive circulation. These structural changes also contribute to the more pronounced falls in blood pressure evoked by most antihypertensive drugs in hypertensive patients compared with normal subjects. In the resistance vessels the hypertrophy of the smooth muscle coat encroaches upon the vessel lumen, so that even after full dilatation of the smooth muscle the resistance to blood flow is higher than in fully dilated normal blood vessels. Folkow first pointed out that the hypertrophied smooth muscle is an 'amplifier' of constrictor stimuli which produces a greater narrowing and large rise in vascular resistance than in the normal circulation (Fig. 12) (Folkow, 1978). In rabbits with cellophane wrap hypertension the vascular amplifier in the hindlimb doubled the rise in resistance produced by a given

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dose of constrictor hormone; the effect appeared to be non-specific with similar amplification produced by noradrenaline, angiotensin II and vasopressin (Angus et al., 1976). Whether the structural changes account entirely for the abnormal constrictor effects in hypertension is not clear at present; abnormalities in local vascular control mechanisms (e.g. prostaglandins) may also play a role. The heart too hypertrophies in hypertension. During the initial 'physiological' phase of this process a given inotropic stimulus is also 'amplified' by the greater cardiac muscle mass compared with its effect in the normal heart (Broughton and Korner, unpublished data). It is probably the amplification of inotropic stimuli by the hypertrophied heart that permits the maintenance of a normal cardiac output in the face of elevation in afterload. Later on, particularly in the presence of coronary artery disease cardiac output tends to fall (Frohlich, 1973). 3. CARDIOVASCULAR F U N C T I O N O F T H E CNS N E U R O N S RELEASING C A T E C H O L A M I N E S , S E R O T O N I N AND SEVERAL OTHER TRANSMITTERS Many different experimental approaches have been used to analyse the effects of the different transmitters particularly in relation to the NA and 5HT neurons. What has been surprising is the diversity of findings by different investigators with often diametrically opposite conclusions about function. Therefore the main methods used and some of the advantages and limitations of the various approaches are briefly considered: (i) Intracerebroventricular fi.c.v.) injection of transmitter or a related agonist. This will simulate only s o m e of the effects of synaptically released transmitter since the concentration of injected transmitter at synapses a long way from the CSF will be too low (Chalmers and Wurtman, 1971). (ii) Microinjections of transmitter into a particular nucleus. The main problem is whether the concentration of injected transmitter is in the physiological range. (iii) Injection of various transmitter precursors by several routes, e.g. L-DOPA, tryptophan or 5-hydroxytryptophan (5HTP). Giving each precursor increases the appropriate transmitter stores of the axon terminal, but it does not follow that there will necessarily be an increased release of transmitter during subsequent neuronal activity. (iv} I.c.v. or local brain injections of selective neurotoxins, e.g. 6-hydroxydopamine (6-OHDA) and 5,6- or 5,7-dihydroxytryptamine (5,6- or 5,7-DHT) (Uretsky and Iversen, 1970: Haeusler et al.. 1972; Baumgarten et al., 1972; Baumgarten and Bjorklund, 1976; Chalmers, 1975). These drugs have mostly been used for assessing chronic changes in function after days and weeks following destruction of a particular group of neurons (e.g. Chalmers and Reid. 1972: Haeusler et al., 1972; Wing and Chalmers, 1973). However, the acute changes occurring in the first few hours after i.c.v, injection provide information aboul the effects of synaptic release of transmitter (Haeusler, 1971, Korner et al., 1978, 1979: Head and Korner, 1980; Korner and Head, 1980). The release of transmitter precedes the stage of neuronal block and destruction of nerve terminals (Haeusler, 1971). The mttior problem with these drugs as analytical tools is that at too low concentrations many terminals escape destruction, whilst at too high concentrations they no longer act specifically but become generalised neurotoxins (Butcher et al., 1974). An additional problem is that with 6-OHDA and 5,6-DHT there are marked changes in eating and drinking behavior which produce a variety of chronic 'non-specific' disturbances in cardiovascular function which tend to confound the 'true' chronic effects that follow destruction of these neurons (Ungerstedt, 1971, Korner et al., 1978). (v) Administration of inhibitors of biosynthetic enzymes, e.g. ~-methyl paratyrosine, parachlorophenylalanine (PCPA). The problem again lies in assessing to what extent these drugs exert specific effects in relation to the particular group of neurons and to what extent they produce non-specific neural effects through actions on other systems (cf lto and Schanberg, 1972; Wing and Chalmers, 1974). (vi) Electrical stimulation of particular nuclei and the effects of localised lesions. Both

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may affect other types of neurons of cardiovascular significance than those releasing the specific transmitter.

3.1. CA AND DA NEURONS The CA neurons were first described in the rat by Dahlstr6m and Fuxe (1964) using the fluorescence histochemical method. CA neurons have their cell bodies in the bulb, whilst the neurons in midbrain and diencephalon which have a similar green fluorescence are believed to synthetize DA as a transmitter, since they lack dopamine/~-hydroxylase required for CA synthesis (H~kfelt et al., 1976; Swanson and Hartmann, 1975). The neurons have been grouped into nuclei numbered from A1 caudally to A13 rostrally, with those from A1 to A8 mostly CA neurons and those from A9 to A13 mostly DA neurons. Their organisation appears to be similar in rat, rabbit and monkey (Dahlstr~Sm and Fuxe, 1964; Garver and Sladek, 1975; Blessing et al., 1978, Loewy and McKellar, 1980). The majority of CA neurons release NA as their transmitter but several release adrenaline. The latter are distinctively grouped in several nuclei (e.g. A1 and A2 and locus coeruleus) in which NA containing neurons are also present. Some CA neurons send ascending axons to numerous regions above the pons, whilst other neurons send their axons to other bulbar nuclei and through descending reticulospinal fibres to the ILN preganglionic sympathetic motoneurons. It is now known that the A5 and A6 nuclei (locus coeruleus and subcoeruleus) are the main source of descending reticulo-spinal fibres (Loewy and McKellar, 1980; Dampney, 1981). Other cells in these nuclei innervate neurons in the bulb, cerebellum, diencephalon and forebrain (Speciale et al., 1978; Loewy et al,, 1979). The following CA nuclei probably play the greatest role in cardiovascular control :--(i) A 1, in the ventrolateral medulla; (ii) A2 in the NTS regions; (iii) A5 and A6 in the dorsal pons. The main role of DA neurons is in the regulation of somatic movement and in the control of eating and drinking behavior (Moore and Bloom, 1978). A direct hypothalamo-spinal DA pathway has recently been described, arising from cells in the dorsal part of the posterior hypothalamus, which includes cells of the A13 nucleus and probably has a cardiovascular function (Blessing and Chalmers, 1979). I.c.v. injection of NA has mostly produced falls in blood pressure and heart rate in both unanesthetized and anesthetised animals (for references see Day and Roach, 1974; Day et al., 1976). Similar responses are evoked by L-DOPA given in the presence of a peripheral decarboxylase inhibitor to assure effects predominantly on the CNS. In the context of the earlier discussion these results suggest that at least some of the actions of NA neurons lower blood pressure and heart rate. In the spinal cord de Groat and Ryall (1967) and Ryall (1967) observed inhibition of activity of preganglionic sympathetic neurons following microiontophoretic injection of transmitter. Another site from which depressor effects have been evoked by microinjections of noradrenaline is the A2 regions of NTS (de Jong et al., 1975). Lesions of area A1 have produced a rapid rise in blood pressure, suggesting that it may subserve a tonic depressor function (Blessing, 1980 and Chalmers, personal communication). The suggestion that descending influences of noradrenergic neurons are depressor is at variance with the conclusions of Neumayr et al (1974) and of Taylor and Brody (1976) who used electrical stimulation of the A1 and A2 nuclei and of spinal descending CA tracts respectively and studied the effects of intrathecal noradrenaline or i.v. L-DOPA on the evoked preganglionic sympathetic discharge. The interpretation of their experiments is critically dependent on the capacity to confine the electrical stimulus to NA cells and fibre tracts. Chalmers and Reid (1972) also concluded that NA neurons tonically increased blood pressure from the chronic pressure changes occurring after i.c.v, of 6-OHDA (see also Chalmers, 1975). Such changes have not been observed by others in the rabbit (Korner et al., 1978) or in the rat (Haeusler et al., 1972). Possibly 'non-specific' fluid balance problems may have contributed to the differences in findings.

P.I. KORNf,R and J. A. AN(;~TS

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Korner et al. (1978) recently demonstrated that some NA neurons increased blood pressure through a suprapontine pathway whilst others exerted a net depressor effect through a bulbo-spinal pathway (Fig. 13). This was based on an analysis of the acute phase of transmitter release over the first few hours of i.c.v. 6-OHDA and the effects of phentolamine on these responses. The pressor response resulting from increased activity of NA neurons with suprapontine axons affects mainly the renal and splanchnic sympathetic outflows (Korner et al.. 1978). The site of suprapontine termination of the NA axons was not determined, but it could be from the hypothalamus where Przuntek et al. (1971) have demonstrated that NA is the transmitter mediating the rise in blood pressure from the posterior hypothalamic pressor region. Changes in reflex function produced during the acute phase of NA release include marked alterations in the rabbit's baroreceptor heart rate reflex properties (Fig. 14) and also in nasopharyngeal constrictor and heart rate reflexes (Korner et al., 1979). During the acute phase of NA release there was considerable facilitation of blood pressuremediated changes in vagal activity, whilst 2 weeks after chronic destruction of NA neurons a small degree of residual vagal depression could be demonstrated (Korner eta/., 1979). Resting blood pressure and heart rate had recovered and the animals had resumed normal eating and drinking so that 'non specific' fluid balance disturbances had largely been corrected. These results suggest that NA neurons participate in the normal reflex function including the baroreceptor heart rate and nasopharyngeal reflex pathways. In summary, the autonomic functions of different groups of NA neurons are not uniform. Those giving rise to bulbo-spinal fibres lower blood pressure, whilst those with suprapontine connections increase blood pressure. Bulbar NA neurons facilitate the activity of vagal motoneurons involved in the baroreceptor heart rate reflex. 3.2. 5HT NEURONS These neurons have been grouped in various nuclei from B1 caudally to B10 rostrally (Dahlstr6m and Fuxe, 1964b; Fuxe et al., 1968; Palkovits et al., 1974). They lie (i) in the midline structures amongst the raphe nuclei of medulla and pons; (ii) in the dorsal pons above the vestibular nucleus and (iii) in the mesencephalon (for references see Kuhn et

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60 I00 140 60 I00 MEAN ARTERIAL PRESSURE (mmHg) FIG. 14. (Top panels): Average baroreceptor-heart rate reflex function curves relating mean arterial pressure (MAP) to heart period (HP) before (control) and 2 hr and 4 hr after i.c.v, injection of 6-OHDA or 5,6-DHT. (Lower panels): Curves obtained before and 14 days after 6-OHDA or 5,6-DHT. Large symbols indicate average resting values (From Korner and Head, 1981, by permission).

al., 1980). Like NA neurons some send descending axons to the ILN sympathetic preganglionic neurons. These reticulospinal fibres come mostly from the n. raphe magnus (Segu and Callas, 1978) with contributions from n. raphe pallidus and obscurus (Loewy and McKellar, 1980; Oliveras et al., 1977). Fibres from other neurons ascend to several brain regions above the pons (Palkovits et al., 1977). Some 5HT cells from raphe nuclei innervate NA cells in the locus coeruleus region (Pickel et al., 1976; Sladek and Walker 1977) (cf Fig. 15). As with NA neurons the evidence suggests that 5HT neurons are not functionally uniform. Thus with electrical stimulation of the B1 B3 medullary raphe nuclei pressor responses were evoked from some regions and depressor responses from others (Adair et al., 1977).

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I.c.v. injections of 5HT have produced rises in blood pressure in some studies and falls in others (McCubbin et al., 1960; Baum and Shropshire, 1975; Lambert et al., 1975: Krstic and Djurkovic, 1976; Kuhn et al., 1980), perhaps because of species differences and/or to differences in doses. In most experiments in rats, where a pressor response has usually been found, the doses/kg have been small compared with those in dogs and cats where 5HT has usually lowered blood pressure. Local microinjection of 5HT has increased firing rates of spinal preganglionic sympathetic neurons (de Groat and Ryall, 1967). Injections in the anterior hypothalamus have produced rises in blood pressure and heart rate (Smits and Struyker-Boudier, 1976) and cardiovascular responses related to thermoregulation (Komiskey and Rudy, 1977). Our group has recently found that in the first few hours after i.c.v, injection of 5,6-DHT many of the responses can be related to synaptic release of 5HT (Korner and Head, 1981). These responses, which include a biphasic rise in blood pressure and a rise in heart rate, are attenuated or prevented by the 5HT antagonist methysergide (Fig. 13). In pontine rabbits the rise in heart rate is similar to that of animals with intact CNS but the late component of the hypertensive response is abolished, indicating that it is mediated through a suprapontine pathway. Other acute effects of i.c.v. 5,6-DHT include some inhibition of baroreceptor reflex mediated activity in cardiac vagal motoneurons (Fig. 14) and changes in nasopharyngeal reflex properties, Chronically after 2 weeks the opposite changes occur, i.e. facilitation of vagal activity (Fig. 14). At that time blood pressure and heart rate had been restored to initial control levels. Transmitter precursors have been used to simulate enhanced activity of 5HT neurons (Kuhn et al., 1980). However, although two precursors, tryptophan and 5 H T P both increase stores of 5HT of neuron terminals, only the latter elicits significant cardiovascular effects (Antonaccio and Robson, 1973; Coote and Mcleod, 1974; Nolan, 1977). l.c.v. (or i.v.) 5 H T P has produced dose-dependent falls in blood pressure in most series (see Kuhn et al., 1980), i.e. which is the opposite to the response produced by giving 5HT. The reasons for the differences are not clear. Wang and Aghajanian (1977) found diminished rates of firing of pontine raphe 5HT neurons evoked by iontophoretic application of 5HT precursors or 5HT and suggest that the inhibitory response was mediated in response to an increase in 5HT availability by a recurrent collateral from the cell's own axons. The irreversible tryptophan hydroxylase inhibitor PCPA induces a rise in blood pressure in the rat (lto and Schanberg, 1972; de Jong et al., 1975; Ogawa, 1978). The rise in pressure starts some hours after parenteral administration and lasts for several days. However, in the dog, cat and rabbit PCPA produces either little change in blood pressure, or a small depressor response (Dunkley et al., 1972; Wing and Chalmers, 1974). Some of these changes may be due to non-specific effects of PCPA (e.g. on eating and drinking). In s u m m a r y , during synaptic release of 5HT blood pressure is raised for several hours through a suprapontine pathway. There is also a more transient rise in blood pressure through a bulbospinal pathway. An acute rise in heart rate occurs owing to inhibition of vagal motoneurons through a bulbar pathway. Chronic changes in baroreceptor-heart rate reflex properties suggest that 5HT neurons are normally active in the pathways subserving this reflex.

3.3, INTERRELATIONSHIPSOF NA AND 5HT NEURONS IN CONTROL OF HEART RATE AND BLOOD PRESSURE This has recently been studied by comparing the acute effects of synaptic release of NA (induced by 6-OHDA) or of 5HT (induced by 5,6-DHT) after destruction one week before the experiment of the neurons belonging to the other transmitter system (Korner and Head, 1981). These studies suggest that NA and 5HT neurons regulate the effects of vagal effector activity on the heart rate through independent parallel bulbar pathways (Fig. 15), with NA neurons facilitating vagal activity and 5HT neurons inhibiting it.

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Though the evidence is not as compelling it seems probable that NA and 5HT neurons which give rise to descending reticulospinal fibres control blood pressure in a similar manner, through independent parallel pathways with antagonistic functions. NA bulbospinal pathways inhibit activity of sympathetic preganglionic neurons whilst 5HT neurons increase it in agreement with the iontophoretic data. By contrast the suprapontine pressor pathway includes a 5HT neuron in series with an NA neuron, as shown schematically in Fig. 15 (cf Sladek and Walker, 1977; Pickel et al., 1977). With the NA neuron further from the bulb than the 5HT neuron i.c.v. 6-OHDA will evoke a pressor response both when 5HT neurons are functioning normally, or when they have previously been destroyed by 5,6-DHT. On the other hand, the sustained component of the pressor response evoked by i.c.v. 5,6-DHT is abolished by previous destruction of NA neurons by 6-OHDA (Korner and Head, 1981). 3.4. OTHER TRANSMITTERS 3.4.1. Glutamate and G A B A (y-aminobutyric acid) Talman et al. (1980) recently obtained evidence suggesting that 1-glutamate is an excitatory transmitter released from baroreceptor afferents in the NTS. They demonstrated that local injections of glutamate produced hypotension and bradycardia. In other words they simulated the effects of stimulation of the baroreceptors. This effect was also produced by low doses of the glutamine analog kainic acid and was antagonised by the selective antagonist glutamine diethyl ester (Reis et al., 1980). After nodose ganglionectomy, with degeneration of afferents to the NTS, there was reduction of the glutamate concentration in the NTS, but no change in the concentration of GABA or of glycine. I.c.v. injections of the important inhibitory transmitter GABA or of its analogue muscimol lowers blood pressure and heart rate (Antonaccio and Taylor, 1977; Antonaccio et al., 1978; Williford et al., 1980), as a result of diminished neural sympathetic activity in the cardiac and constrictor outflows; the site of transmitter action appears to be in the hindbrain. Recent studies by Barman and Gebber (1979) suggest that GABA might be the transmitter involved in a suprabulbar pathway that tonically inhibits vagal tone. Picrotoxin and bicuculline lowered basal heart rate in spinal but not in decerebrate cats, suggesting that GABA is an inhibitory transmitter involved in the reduction of vagal tone in the pathway from the hypothalamic defence area and from a number of other hypothalamic sites. This pathway may be generally involved in the suprapontine inhibition of tonic vagal activity. 3.4.2. Angiotensin There has been great interest in the role of angiotensin II (AII) on the CNS autonomic pathways. Many of the experiments have involved i.c.v, or close vertebral artery injections of AII. The extent to which the effects observed by the often large doses used are relevant to any effects exerted by changes in circulating AII on the CNS, is not yet resolved. Moreover, the brain has the capacity of generating angiotensin-like material in situ (Reid, 1977). The brain renin system has been implicated as a causal mechanism in elevating blood pressure of the Okamoto-Aoki strain of genetically hypertensive rat (Ganten et al., 1979). Buckley and colleagues (see Buckley and Vollmer, 1976) showed that AII given by the i.c.v, route in the dog caused a pressor response mediated through neurons lying in the mesencephalon. Ferrario et al. (1969, 1970) showed that AII receptors of cardiovascular importance were present in the hindbrain; later they were localized to the area postrema region (Joy and Lowe, 1970; Ferrario et al., 1979) and AI! receptors have been demonstrated in this area by membrane binding studies (Sirett et al., 1979). In mongrel dogs the action of AII on this site is mainly to increase the level of sympathetic nerve activity in both cardiac and constrictor outflows, but in the greyhound there is also inhibition of

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cardiac vagal activity (Scroop and Lowe, 1969; Ferrario et al., 1972). In the sheep the central action of i.v. infusions of AII inhibit cardiac vagal activity under conditions when rises in blood pressure are prevented by simultaneous infusions of vasodilators (Lee et al., 1980). Based on their extensive recent analysis Ferrario et al. (1979) consider that AII receptors in the area postrema in the dog are associated with neurons that enhance the level of sympathetic activity in response to changes in circulating All concentrations. The area contains NA neurons (Torack et al., 1973). The studies of Lewis et al. (1973) suggest that these may be involved in the CNS action of AII since the pressor response to J.c.v. injection of AII was attenuated by previous treatment with 6-OHDA. Ferrario et al. (1979) have also produced lesions of the area postrema. The main chronic change was the disappearance of the pronounced respiratory cardiac arrhythmia that is so characteristic in the resting conscious dog. This accounted for the reduction in variability of stroke volume and cardiac output, but there were no chronic changes in variability of blc~od pressure.

3.4.3. Opioid Peptides and Substance P The enkephalins were discovered after the description of binding sites for opiate narcotic drugs within the CNS (Kosterlitz and Hughes, 1975). These, and other peptides including the endorphins and substance P, have since been found in many parts of the brain and in the peripheral nervous system (Tregear and Coghlan, 1980). The enkephalins and endorphins are the 'natural' ligands of opiate receptors in the brain and in view of their demonstration inside neurons by immunohistochemical procedures they have been proposed as transmitters. Enkephalins and endorphins are each found in distinct regions of the CNS, though there are areas that contain both. The highest concentration of enkephalins is in the corpus striatum, whilst the pituitary gland is the main source of /:¢-endorphin. Naturally much interest has focused on their actions on afferent systems. For example, it has been shown that microiontophoretic injections of metenkephalin inhibit firing of spinal substantia gelatinosa neurons (Duggan, 1980). From the cardiovascular viewpoint it is of interest to determine to what extent their actions resemble those of morphine and its analogs. In the dog morphine produces marked bradycardia (due to reduction in cardiac sympathetic activity and some increase in vagal activity) and a fall in blood pressure associated with reduction in sympathetic constrictor activity (Schmitt and Laubie, 1979). ~q-endorphin given cisternally first evokes a rise in blood pressure and heart rate followed by sustained falls in those variables (Schmitt and Laubie, 1979). A potent hypotensive action of fl-endorphin has been demonstrated by Lemaire et al. (1978). This may be mediated through a 5HT mechanism, since the fall in blood pressure was reduced by pretreatment with PCPA and was potentiated by the 5HT uptake inhibitor fluoxetine. Leucine enkephalin raises blood pressure and heart rate when injected into the lateral ventricle or cisterna in both cats and rats and the changes were antagonised by naloxone (Schaz et al., 1980). Moreover in genetically hypertensive rats leucine enkephalin evoked increases in ACTH, ADH and catecholamine secretion (see Schaz et al., 1980). In the dog d-ala enkephalinamide produced first a rise in blood pressure and heart rate followed after several minutes by a marked fall (Schmitt and Laubie, 1979). In the cat the rises in blood pressure and heart rate were more prolonged (Schaz et al., 1980), there was considerable depression of the vagal component of the baroreceptor-heart rate reflex. Marked pressor effects have also been observed after i.c.v, injection of substance P (Fuxe et al., 1979). It is too early to say to what extent these actions reflect physiological effects of the above peptide transmitters. In sensory systems a favored hypothesis has been that the enkephalins are released at axoaxonic synapses and reduce transmitter release by primary afferent depolarisation (Duggan, 1980). On the other hand it has been proposed that the enkephalins and endorphins may act as 'modulators', i.e. as substances that do

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not affect cell excitability per se but modify the actions of other transmitters (Barker, 1978). 4. MECHANISM OF ACTION OF SOME ANTIHYPERTENSIVE DRUGS It has recently become apparent that sustained reduction in blood pressure over minutes or hours produce rapid resetting of the arterial baroreceptors through alterations in the receptors themselves (Dorward et al., 1980). They will then signal merely the changes about the new blood pressure level without 'remembering' the previous level of absolute blood pressure. This type of peripheral resetting should be distinguished from central resetting due to afferent interactions or changes in transmitter release discussed earlier. Rapid arterial baroreceptor resetting has the effect of limiting the time course and magnitude of reflex autonomic responses evoked by changes in blood pressure (Korner and Oliver, 1980; Dorward et al., 1980). An important element of all therapy is to produce a fall in blood pressure that is sufficiently long sustained to minimize the effectiveness of the body's homeostatic mechanisms which normally compensate for transient changes in blood pressure. Such resetting of the arterial baroreceptor and reflex properties is of particular importance in longterm antihypertensive therapy with vasodilators and diuretics, i.e. with drugs that have their major actions outside the CNS. This section considers the mechanisms and sites of action of drugs with major actions in the CNS. Drugs such as clonidine and a-methyl dopa also have actions on the peripheral sympathetic neuron which involve some of the same pharmacological mechanisms as their actions in the CNS. In addition, they act on other components of the neural control system, e.g. the arterial baroreceptors. The important question is which of these various actions contribute to the drugs' effects in lowering blood pressure in the normal therapeutic dose range. 4.1. CLONID1NE

4.1.1. Peripheral Actions Clonidine is a weak vasoconstrictor agent which stimulates postsynaptic ~-adrenoceptors (Kobinger, 1978). It can be considered a 'partial' agonist (Ariens, 1964), since its maximum constrictor action is only about 30 per cent of that of noradrenaline or phenylephrine (Ruffolo et al., 1979). This accounts for the small initial pressor response observed during rapid i.v. administration in man or animals. As a partial agonist it has the capacity for becoming an antagonist of the effects exerted by the normal transmitter noradrenaline, but this action only begins at concentrations of about 5 ng/ml i.e. 2.2 × 10-aM which is well above the range of concentrations encountered in therapy (Ruffolo et al., 1979). The action of the drug in modulating release of sympathetic transmitter through presynaptic mechanisms occurs, however, at relatively low concentrations of clonidine (10-9-10 -8 M, i.e. 0.23-2.3ng/ml, see Fig. 16). For example, in the guinea pig right atrium the tachycardia evoked by sympathetic nerve stimulation is markedly attenuated by clonidine; pretreatment with phentolamine or yohimbine antagonises this action competitively. This presynaptic modulatory action of clonidine has been generally interpreted as an action on a presynaptic ~-adrenoceptor which inhibits NA release. The receptor in question has been classified as an ~2-adrenoceptor, because of some differences in its properties from the postsynaptic or ~l-adrenoceptor. Since the receptor involved in the presynaptic action of clonidine does not seem readily accessible to synaptically released NA (Fig. ll) we feel that caution is indicated in regarding the clonidine receptor as an or-receptor, despite the competitive antagonism by phentolamine and yohimbine. The presynaptic modulatory effect of clonidine on transmitter release appears to be of therapeutic relevance. Oral doses of 150-300 ~g to patients with essential hypertension

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FIG. 16. Relationship between number of field pulses applied to guinea pig right atrium preparation (+ atropine 1 #Mt (1 pulse/successive refractory period) on tachycardia response expressed as a fall in period (ms). (Left): effect of different concentrations of clonidine ( x 10 9 M) on dose-response curve. (Right): effect of clonidine in the presence of 10 -7 phentolamine (From Korner et aL, 1981).

leads to plasma levels of 0.9-2.5 ng/ml (i.e. 3.9 x 10 - 9 1.1 x 10 -8 M) (Wing et al., 1977). This concentration is sufficient to reduce the sympathetically mediated NA release in the guinea pig atrium (Fig. 16). If the attenuation of transmitter release at constrictor nerve terminals was similar this would contribute appreciably to the drug's antihypertensive action. This has been considered improbable by Reid et al. (1977) in view of their failure to evoke significant falls in blood pressure following clonidine in tetraplegic patients with complete cord transections above the level of the sympathetic outflow. Such patients probably have low levels of resting sympathetic tone (Freyschuss and Knutsson, 1969; Corbett et al., 1971) even though sympathetic responses can be reflexly evoked. Without at least normal levels of resting tone it would be difficult to demonstrate peripheral modulation of transmitter release. Clonidine also 'sensitizes' the arterial baroreceptors, so that a unit fires more at a given blood pressure than before the drug (Aars, 1972; Korner et al., 1974). It is not known whether the effect involves a direct action of clonidine on the receptor or whether it is the result of interruption of sympathetic feedback to the vessel wall. The sensitization occurs at relatively high doses of clonidine and it is doubtful whether it contributes significantly to the therapeutic action. 4.1.2. C N S actions Administration of clonidine by i.c.v, or i.v. routes lowers blood pressure and heart rate in man, dog, cat and rabbit and reduces release rate of catecholamines (Kobinger, 1978; Schmitt and Laubie, 1978; Korner et al., 1981). In the rabbit, cisternal injection is about 30-40 times more potent than i.v. administration, emphasising the importance of CNS mechanisms in these effects. Cardiac slowing results from both increased vagal and reduced cardiac sympathetic activity (Korner et al., 1974). In sino-aortic denervated preparations the fall in blood pressure is greater than in the intact animal, but this is accounted for by the neurogenic hypertension in these preparations. After sino-aortic denervation the bradycardia evoked by clonidine is about half that observed in intact animals. In sino-aortic denervated rabbits vagal tone is almost completely abolished, so that the residual bradycardia is mainly sympathetically mediated (Korner et al., 1981). As a result of its CNS actions clonidine markedly alters the properties of baroreceptor reflexes. There is resetting of the baroreceptor-heart rate reflex M A P - H P function curves so that there is dose-related reduction in threshold for evoking bradycardia and an increase in gain and HP Range (Fig. 17). The effects of arterial pressure on vagal activity are facilitated (Kobinger and Walland, 1972, Korner et al., 1974; Antonaccio et al., 1975; Myers, 1977). The drug also alters the properties of the cardiac sympathetic component

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of the reflex. At high doses of clonidine the cardiac sympathetic is almost completely inhibited and becomes very unresponsive even to large arterial pressure changes (Korner et al., 1974). However, very strong afferent 'drive', e.g. that produced by arterial chemoreceptor-baroreceptor interactions in arterial hypoxia in the rabbit can antagonize these inhibitory effects of clonidine (Shaw et al., 1971). Sympathetic constrictor baroreceptor reflexes have been studied in anesthetized preparations (Haeusler, 1974; Dorward and Korner, 1978). The drug produces dose-related lowering of the pressure threshold for evoking sympathetic inhibition, resulting in a lower degree of neural activity at a given MAP than before the drug (Fig. 18). At low doses of clonidine the resting sympathetic constrictor discharge is only slightly lowered but at high doses there is often .pronounced inhibition of sympathetic activity. Another important neurally mediated effect of clonidine is to produce reduction in the rate of renin secretion (Ganong and Reid, 1975). There is general agreement that the great majority of CNS-mediated cardiovascular autonomic effects of clonidine are produced through actions in bulb and spinal cord. Thus bradycardia, hypotension and resetting of the baroreceptor-heart rate reflex can all

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be evoked by clonidine in decerebrate preparations. with the magnitude of the effects similar to those observed in intact animals. These bulbospinal actions of clonidine closely resemble the changes produced by the release of noradrenaline from bulbar and spinal noradrenergic neuron terminals (see Section 3.1). Clonidine. however, does not simulate any of the suprapontine effects of transmitter release from NA neurons. suggesting some differences in receptor mechanisms involved. It is possible that there are distinctive populations of bulbospinal and suprapontine a-adrenoceptors. or alternatively that clonidine acts on imidazoline receptors located on the same bulbospinal neuron that also have cx-adrenoceptors. We favor the second of these hypotheses for reasons discussed in relation to the apparent differences in ‘noradrenaline’ and ‘clonidine’ presynaptic receptars at the sympathetic endings of the guinea pig atrium (Figs 11 and 16) (Angus and Korner, 1980). There has been controversy regarding the importance of NA neurons in relation to the actions of clonidine, with some believing that they play little role (Haeusler and Finch, 1972; Kobinger and Pichler, 1975; Warnke and Hoefke. 1977) whilst others consider that they are of importance (Dollery and Reid, 1973; Reynoldson et al.. 1979). In the conscious rabbit Reynoldson rf al., 1979 found that following 6-OHDA induced chronic destruction of NA neurons there was complete abolition of the major component of the bradycardia and reduction in the late component normally evoked by i.c.v. bolus injections (Fig. 19, middle panels). However, there was no change in the hypotensive response to i.c.v. clonidine. in agreement with the findings of Kobinger and Pichler (1975) and Warnke and Hoefke (1977). Following destruction of 5HT neurons with 5,6-DHT both the bradycardia and hypotension were attenuated (Fig. 19, right panels) (Korner rt al., 1981). Using single unit recording Svensson et N/. (1975) have shown that clonidine inhibits NA neurons of the area postrema and 5HT neurons in the midbrain raphe nuclei. There is thus an electrophysiological basis for postulating that clonidine can produce direct inhibition of both types of neurons. Mention must be made of the possible role of histaminergic neurons of the CNS in the hypotensive response to clonidine, since this has been attenuated following administration of the H,-receptor antagonist metiamide (Karppanen et al., 1976; Finch rt (I/., 1978). Thus, clonidine closely simulates the cardiovascular actions of synaptically released NA from bulbospinal terminals. NA neurons contribute to the bradycardia, whilst 5HT

Blood pressure control and antihypertensive drugs

343

neurons are involved in both the bradycardia and hypotension. Histaminergic neurons may also contribute to the hypotension. The findings with the different neurotoxins suggest that the CNS effects of clonidine are probably mediated through more than one locus of action in the bulbospinal regions of the brain. Anatomical localisation studies have suggested that at least part of the drug's action is mediated through NTS neurons (Laubie et ah, 1976; de Jong et ah, 1979; Lipski et ul,, 1976). Other suggested sites of action are in the ventral or ventrolateral area of the brainstem (Bousquet et al., 1975; Bousquet and Guertzenstein, 1973) and in the spinal cord [McCall and Gebber, 1976). There is little evidence that suprapontine brain regions are an important site for any of the major cardiovascular actions of clonidine (Kobinger, 1978). Abrupt cessation of clonidine therapy may provoke a 'rebound' effect, closely resembling a crisis in a phaeochromocytoma, which has tended to limit the drug's clinical use (Hunyor et ah, 1973). The phenomenon consists of a marked elevation of blood pressure and heart rate and an increased catecholamine release. The extreme 'rebound' phenomenon is a relatively unusual occurrence perhaps because of the efficiency of blood pressure homeostatis. In the experience of Reid et al. (1977) rises in blood pressure and elevation of plasma catecholamines occurred in most patients and we have observed some rise in blood pressure and a large increase in urinary catecholamine excretion in the first 24 hr after clonidine withdrawal in each of six patients. The effect can be reversed by autonomic blockade (Reid et ah, 1977). Rebound can be produced in experimental animals, and in these blood pressure rise was maximal 16-24 hr after the last injection and sometimes occurred even after a single dose of clonidine (Oates et al., 1978). The exact mechanisms involved in clonidine rebound are unknown. It occurs less often with other antihypertensive drugs (e.g. :~-methyl dopa) believed to act at similar CNS sites (McMahon, 1978). 4.2. GUANFACINE

This is a ~second generation' clonidine-like compound which has very similar pharmacological actions to clonidine (Scholtysik, 1980). Thus, it constricts peripheral vessels and reduces transmitter release from presynaptic endings through actions at presynaptic receptor sites (Scholtysik et al., 1975, Pacha et al., 1975). It slows the heart, lowers blood pressure and has a facilitatory action on baroreceptor reflex mediated bradycardia. All the latter actions can be produced by i.c.v, injection of small doses of guanfacine, suggesting that they are mediated through CNS mechanisms. Cessation of treatment produces "rebound'. There may be some differences in the CNS sites of actions between guanfacine and clonidine. Thus application of clonidine (2/~g/kg) to the ventral surface of the medulla lowered blood pressure and heart rate but application of guanfacine (20/~g/kg) was without effect, Metiamide appears to be without effect on the hypotensive response to guanfacine though antagonizing that produced by clonidine (Karppanen et ah, 1980). Apart from these relatively minor differences, guanfacine and clonidine have very similar actions. 4.3. ~-METHYL DOPA

The theories about this commonly used antihypertensive agent include:--(i) its action in the CNS through stimulation of 2-adrenoceptors; (ii) its action as a 'false' transmitter, where ~-methyl NA replaces NA in both the CNS and peripheral NA terminals; (iii) reduction in the peripheral and central noradrenaline stores (Porter et al., 1961); (iv) the inhibition of dopa decarboxylase. It is generally thought that the main antihypertensive action of ~-methyl dopa follows its metabolism to e-methyl NA (Henning, 1969). However, it is possible that the 3-0-methylated metabolite may also contribute to its antihypertensive action, particularly after prolonged administration (Zavisca et ah, 1979).

344

P.I. KORNERand J. A. ANGUS

Peripherally, a-methyl NA has a weaker pressor activity in man than NA, but has virtually the same potency as the latter in the pithed rat preparation (Mueller and Horwitz, 1962; Finch et al., 1975). Its effects on presynaptic sympathetic terminals have been tested in the rabbit pulmonary artery preparation, using labeled overflow of noradrenaline. In this preparation a-methyl NA had a more potent presynaptic effect on transmitter release than clonidine (Starke et al., 1975). However, in the guinea pig atrium preparation a-methyl NA was without effect on the sympathetically mediated tachycardia response (unpublished data). Many of the actions of a-methyl NA that are mediated through its CNS effects resemble those produced by clonidine. Thus, it lowers heart rate and blood pressure mainly through actions in the bulb and/or spinal cord, and these actions can be antagonized by i.c.v, phentolamine, yohimbine and piperoxane (Heise and Kroneberg, 1972; Finch et al., 1975). c~-methyl dopa also reduces renin secretion (Mohammed et aL, 1969). Some of the effects are mediated through NTS neurons (de Jong et al., 1979), as with clonidine, but others are not. For example, after destruction of central NA neurons with 6-OHDA the hypotensive action of a-methyl NA is abolished (Finch and Haeusler, t973) whilst that of clonidine is not affected (Haeusler and Finch, 1972; Korner et al., 1981). Its actions on the baroreceptor-heart rate reflex have, to our knowledge, not been investigated quantitatively, but in its clinical use it lowers heart rate less than clonidine or guanfacine, suggesting some difference in the locus of action. It also reduces NA release rates considerably less than clonidine (Dollery et al., 1979; Esler et al., 1981). 4.4. fl-ADRENOCEPTOR BLOCKING DRUGS

Although propranolol was introduced into the clinical treatment of hypertension over 16 years ago (Prichard and Gillam 1964) the mechanisms by which these drugs lower blood pressure is still controversial. The following theories have been developed to explain their antihypertensive actions: (i) through reduction of sympathetic drive to the heart (+ unmasking of vagal drive) by blockade of postsynaptic cardiac fl-adrenoceptors, thereby reducing cardiac output; (ii) through blockade of presynaptic/:/-receptors in the sympathetic terminals of the heart and blood vessels; (iii) through reduction of renin secretion by blockade of fl-adrenoceptors in the juxtaglomerular apparatus; (iv) through blockade of fl-receptors in the CNS; (v) through sensitization (peripheral resetting) of the arterial baroreceptors. A very large number of fl-blocking drugs are now available in addition to propranolol (e.g. pindolol, timolol, acebutol, sotalol, atenolol). The active stereoisomer of all drugs is the 1-form (Kelliher and Buckley, 1970). These drugs vary in potency, largely because of differences in plasma protein binding (e.g. 90 per cent for propranolol, 40 per cent for pindolol, 10 per cent for timolol [Coltart and Shand, 1970; Jennings et al., 1980; Bobik et al., 1980a]), and in bioavailability. 4.4.1. Time-course of blood pressure reduction When propanolol is administered by the i.v. route in man, to obviate the 'first pass' hepatic clearance effect, heart rate and cardiac output fall immediately, with little further change with successive injections, but the initial fall in blood pressure is small (Fig. 20) (Tarazi and Dustan, 1972; Korner, 1976). There is usually a rise in total peripheral resistance (TPR). Since plasma adrenaline levels at rest are usually insufficient to stimulate fl-adrenoceptors in skeletal muscle with resultant vasodilatation, the rise in TPR can be regarded as a 'compensatory' reflex phenomenon evoked by the initial fall in blood pressure. It is possible that the rather long duration of the elevated TPR, particularly in some subjects, depends on afferent interactions (e.g. between arterial and cardiopulmonary baroreceptors, Section 2.3) producing CNS resetting of baroreflex properties. The major hypotensive response in the patient shown in Fig. 20 required several i.v. doses of propranolol and was associated with a fall in TPR. following an initial rise. It occurred

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after about 12 hr following the first injection. Tarazi and Dustan (1972) have shown that in typical 'responders' to propranolol therapy the major fall in blood pressure usually occurred some time after the initial i.v. dose. It took hours, days or even weeks of oral therapy before maximum blood pressure falls occurred and this was associated with reduction in TPR either to initial resting or below (cf Fig. 20). The latter was often associated with some restoration of cardiac output, presumably owing to the reduction in cardiac afterload and the rise in filling pressures; it occurred despite maintained cardiac slowing. On the other hand 'non-responders' to propranolol generally maintained an elevated TPR for considerable periods, and they too showed characteristic cardiac slowing. Clearly the relationship of the time-course of the blood pressure lowering action of propranolol to its pharmacokinetics is more complex than, for example, that of clonidine. It suggests that attainment of a full hypotensive response may involve actions at a number of fl-receptor sites or through other mechanisms. 4.4.2. Peripheral actions In man only low plasma concentrations of fl-blocking drugs are required to produce maximum slowing of the resting heart rate or to produce inhibition of the sympathetic component of the exercise tachycardia (Colthard and Shand, 1970; Jennings et al., 1980; Bobik et al., 1980). With increasing doses and higher plasma concentrations the drugs' duration of action increases markedly and falls in blood pressure become larger and sustained for longer (Bobik et al., 1981). In the rabbit a plasma concentration of about 40 ng/ml (i.e. in the low therapeutic range in man) produced a 40 fold shift in isoprenaline-heart rate dose response curve and maximum reduction of resting heart rate and cardiac output (Korner et al., 1980). However, with this concentration there was only a minimal reduction in blood pressure over a 3 hr experimental period. It has been suggested that one mechanism of action of fl-blocking drugs is to block a presynaptic fl-adrenoceptor. Normally stimulation of this receptor has been considered

346

P.I. KORNr~R and J A. AY(;t,s

to enhance sympathetically mediated transmitter release (Rand et al., 1975: Langer et al., 1980). It has also been suggested that circulating adrenaline (which has a greater affinity for the receptor than NA) may enhance transmitter release through such a mechanism and be causally involved in the pathogenesis of some types of hypertension (Rand et ,~l., 1980). At the present time a significant role for the presynaptic//-receptor in sympathetic transmission under physiological and patho-physiological conditions still remains to be established (Langer et al., 1980). Administration of propranolol produces rapid reduction in plasma renin concentrations, but the blood pressure fall takes a much longer time period. /]-adrenoceptor blocking drugs with little intrinsic sympathomimetic activity (ISA) (e.g. propranolol, timolol) produce rapid reduction in plasma renin levels by blocking the neural influences on renal juxtaglomerular//-receptors (Ganong and Reid, 1976). However, pindolol, which has pronounced ISA, elevates plasma renin levels (Stokes et al., 1976; Weber et al., 1974). Since drugs with and without ISA appear to be equally effective in lowering blood pressure (Stokes et al., 1976) it seems that inhibition of the renin-angiotensin system is not important except in patients where renin levels are markedly elevated. Maxwell (1979) has recently suggested that some of the high correlations that have been observed in clinical studies between blood pressure lowering action of//-blockers and initial renin levels were due to the inclusion of patients on extremely low and extremely high sodium intakes. In anesthetized animals propranolol has been found to have relatively small effects on arterial baroreceptor discharge but the direction of the change has not been uniform. In the intact rabbit aortic baroreceptors Dorward and Korner (1978) found a small but consistent reduction in integrated discharge of the whole nerve at any given pressure (Fig. 21). This was accounted for by a small reduction in firing frequency (spikes/sec) in aortic baroreceptor units near their threshold pressure, largely due to the reduction in heart rate. Friggi et al. (1977) using whole nerve found a small increase in firing as did Angell-James et al. (19801 who studied baroreceptor units in an artificially perfused aortic arch preparation. The reason for the different findings is not clear; the degree of operative intervention was far less in the study of Dorward and Korner (1978) than those of Friggi et al. (1977) and Angell-James et al. (1980). 4.4.3. C N S a c t i o n s /j-adrenoceptors have been demonstrated on the membranes of many neurons in the CNS (Iversen, 1977). It has long been postulated that at least part of the fall in blood pressure is mediated through CNS mechanisms. Early studies reported falls in blood pressure after i.c.v, injections of relatively large doses of drugs (Kelliher and Buckley, 1970; Day and Roach, 1974; Reid et al., 1974). With these doses leakage of drug occurs from the CSF into the systemic circulation producing/J-blockade of postsynaptic cardiac //-receptors of several hours duration (Anderson et at., 1977). Under these conditions any CNS action tends to become confounded with the peripheral actions of the drug. Another approach has been to study the effects of/~-blocking drugs on evoked reflex responses in man and animals, including changes in the baroreceptor heart rate reflex, the blood pressure response to tilting and the carotid occlusion response (Dunlop and Shanks, 1969; Sleight et al., 1971; Esler and Nestel, 1973; Korczyn and Goldberg, 1974). Alterations of these responses by the drug is difficult to interpret unequivocally in the absence of detailed knowledge about the afferent mechanisms. Furthermore attenuation of the heart rate response to carotid occlusion resulting from the action on cardiac /~-receptors will tend to attenuate the blood pressure response and may be misinterpreted as an impaired constrictor effect. More definite evidence of CNS involvement has come from the correlation between propranolol or pindolol-induced falls in blood pressure and reduction in resting splanchnic sympathetic nerve discharge (Lewis and Haeusler, 1975; Clark, 1976; Friggi et al., 1977). Dorward and Korner (1978) found that resting renal sympathetic nerve discharge

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of anesthetised rabbits was not altered by propranolol, but that there was lowering of the threshold pressure for producing baroreceptor reflex-mediated inhibition of sympathetic nerve activity (Fig. 21). The effect occurred at relatively high plasma levels, > 250 ng/ml. The 'resetting' of the renal baroreflex function curve was not due to 'sensitization' of the arterial baroreceptors. It was not influenced by vagotomy, i.e. did not involve vagal cardiopulmonary afferents. It was not simulated by producing similar falls in blood pressure with haemorrhage or nitroprusside. Therefore these changes were interpreted as indicating a CNS effect of propranolol. Similar changes in baroreflex function curves have been observed in the conscious rabbit (Korner et al., 1980). The effects of propranolol on the renal baroreflex curve are qualitatively similar to those of clonidine (cf Figs 18 and 21). This suggests unmasking of tonic activity of CNS ~-adrenoceptors and that tonic stimulation of fl-adrenoceptors increases blood pressure. The latter is supported by the findings of Day et al. (1976) who showed pressor responses after i.c.v, injections of isoprenaline or salbutamol. If we assume that the transmitter subserving tonic CNS fl-adrenoceptor stimulation is NA, the physiologically important fl-adrenoceptors are probably located in suprapontine brain regions (see Section 3.1). Because the reflex changes occurred mainly at high plasma levels of propranolol we studied the effects of three plasma concentrations (about 40, 90, >200ng/ml) and a control infusion of dextrose all given over a 3 hr period, on the haemodynamic responses of conscious rabbits (Fig. 22). All animals received each infusion on different days. Cardiac slowing and reduction of cardiac output was produced by the lowest plasma concentration with no further augmentation of response at the higher doses. Significant falls in blood pressure over the 3 hr observation period occurred only at plasma concentrations t>90 ng/ml. At the lower plasma levels presumably compensatory increase in TPR tended to minimise reduction in blood pressure. The central nervous 'resetting' of baroreflex function prevented this compensatory rise in TPR thus allowing the fall in blood pressure (which was largely accounted for by reduction in cardiac output) to become manifest. Other recent studies suggesting a CNS action of propranolol include the demonstration in anaesthetised dogs that small i.c.v, doses of the drug greatly attenuated the rises in blood pressure and heart rate that was acutely evoked by sino-aortic denervation (Montastruc and Montastruc, 1980). This propranolol-mediated effect was abolished by ji>l

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pretreatment with i.c.v 6-OHDA, suggesting that NA neurons were involved in the CNS action of propranolol. Which parts of the brain are involved is at present unknown. From the relatively small magnitude of the effects on blood pressure and baroreflex properties compared with those produced by clonidine it seems that the locus of action must be at a greater distance from the major inputs in the NTS region and also at a greater distance from the preganglionic sympathetic motoneurons than the sites of action of clonidine. Some suggestions that suprapontine brain regions might be involved comes from the work of Garvey and Ram (1975) who injected propranolol and pindolol directly into various brain regions and obtained maximum falls in blood pressure following injections into hippocampus and septum. Very large drug doses were used in these local injections and the results require considerable additional evaluation. A strong argument against a CNS action of/3-adrenoceptor blocking drugs has been that agents with poor penetration into the CNS (e.g. atenolol) are just as effective antihypertensive agents as drugs like propranolol with good penetration. Van Zwieten and Timmermans (1979) have recently found that administration of atenolol by close intervertebral artery injection is associated with much more penetration into the brain than when given by the i.v. route. Indeed, drugs can by-pass the blood brain barrier due to leaks in the area postrema and pituitary regions so that considerable amounts can enter the CSF. The possibility that atenolol may have an action on the CNS autonomic pathways must therefore still be considered open. 4.5. SUMMARY We still know little about the exact anatomical sites of action in the CNS of the antihypertensive drugs, quite apart from problems of exact definition of the receptors

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involved. Clonidine and guanfacine lower blood pressure through (i) actions in bulbospinal parts of the brain, particularly those related to the CNS baroreceptor reflex pathways and (ii) through presynaptic mechanisms of the peripheral sympathetic neuron through which NA release is reduced, a-methyl dopa (i.e. its active metabolite a-methyl NA) also acts on bulbospinal mechanisms; some of its effects are similar to those produced by clonidine. It differs from the latter drug in that central NA neurons subserve the fall in blood pressure and in its lack of presynaptic modulatory action in the atrial preparation. The fall in blood pressure produced by propranolol and other /3-receptor antagonists probably depends on the development of adequate drug concentrations at different /3-receptors in the body. Present evidence suggests that blood pressure is lowered (i) through blockade of cardiac /3-adrenoceptors and reduction of cardiac output; (ii) through CNS resetting of constrictor reflexes which cuts short the compensatory rise in TPR and allows the effects on cardiac /3-receptors to become manifest. Drugs without ISA lower plasma renin and angiotensin II concentrations through their peripheral actions and this may contribute to reduction of blood pressure in patients with very high renin levels. 5. C O N C L U D I N G REMARKS AND SUMMARY This account has considered only very briefly the pathways involved in the CNS control of autonomic cardiovascular effectors. Our knowledge of the functions of the different nuclei is still incomplete with respect to the following :--(i) the projections that they receive from peripheral afferents and other regions of the brain; (ii) the transmitters that they release at their terminals and (iii) the contribution that they make to the level of resting and phasic activity in the different peripheral autonomic effectors. However, we do know that virtually every integrative operation by the autonomic pathways of the CNS involves suprapontine as well as lower brain regions. In the intact organism environmental disturbances affecting the circulation often produce simultaneous changes in the activity of several groups of peripheral afferents. As a result of interactions between different pathways in the CNS the reflex autonomic responses to a particular input may become greatly altered by the level of activity in one or more of the other inputs, or by CNS 'command' mechanisms. Interactions of particular importance are those that alter the properties of arterial baroreceptor reflexes. Central 'resetting' of these reflexes results in changes in sensitivity and may be associated with changes in the level of tonic autonomic activity. These central interactions are particularly important in longer term operation of the blood pressure control system, since it has recently become apparent that the peripheral arterial baroreceptors adapt very rapidly to sustained alterations in blood pressure (peripheral arterial baroreceptor resetting). there have been some recent developments about the role of different CNS transmitters in the regulation of autonomic function. Most information relates to the NA and 5HT neurons. Neurons releasing one of these transmitters do not have uniform effects on blood pressure and the NA and 5HT neuron groups are each a very complex system. Acute increases in transmitter release can produce CNS resetting of the properties of arterial baroreceptor reflexes; after destruction of a particular neuron group by means of selective neurotoxins chronic alterations in baroreceptor reflex properties are evident, indicating that those neuron groups normally are an integral component of the CNS autonomic pathways. There are still formidable methodological problems to be resolved to unravel the many roles of these and the other neurotransmitter systems. It is becoming clearer that neurons which release GABA, glutamate and various peptide transmitter at their endings also contribute to autonomic cardiovascular regulation. It seems reasonable to suppose that as many different transmitters will turn out to participate in the regulation of autonomic function as are involved in the control of somatic sensory and motor functions.

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The CNS mechanisms involved in the antihypertensive actions of clonidine, ~-methyl dopa and e-methyl NA resemble some but not all of the actions of synaptically released NA. There are differences in the types of CNS neurons involved in their actions and also in some of their actions on the peripheral sympathetic neuron. For these reasons it seems probable that there may be differences in the CNS and peripheral receptor mechanisms involved in the actions of these so-called central ~-adrenoceptor stimulating drugs. As regards the mechanisms involved in the actions of/3-adrenoceptor blocking drugs the best hypothesis available on present evidence is that their actions involve a combination of actions on peripheral and central/~-adrenoceptors. A major task is the more precise localisation in the CNS of the main sites of actions of the presently available antihypertensive drugs and the examination of interactions with neurons releasing other transmitters which may converge on a particular group of nuclei. Indeed, these drugs are probes for unravelling function of the central autonomic pathways. It may become possible to manipulate the central cardiovascular autonomic mechanisms more selectively than at present, for example, in preventing cardiovascular changes accompanying certain types of behavioral stress. This presents the neuropharmacologist with both a challenge and an opportunity. Acknowledgments This work was supported by the National Health & Medical Research Council. the Life Insurance Medical Research F u n d of Australia and New Zealand, the National Heart Foundation of Australia and the Alfred Hospital Research Fund. We are grateful to Ms. M. Delafield and Ms. M. Scott-Murphy for their help in the preparation of this manuscript.

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