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Cardiovascular Physiology Neural Control Mechanisms: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980
Cardiovascular Physiology Neural Control Mechanisms: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980
Cardiovascular Physiology Neural Control Mechanisms: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980
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Cardiovascular Physiology Neural Control Mechanisms: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980

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Cardiovascular Physiology Neural Control Mechanisms contains the proceedings of the symposia of the 28th International Congress of Physiology held in Budapest between 13 and 19 of July, 1980. Organized into six parts, this book begins with an elucidation of the integrative role of the autonomic nervous system in the regulation of cardiovascular function. Parts II and III explain neural reflex control of the heart and cerebral blood flow regulation. Nervous control of the microcirculation and control of vascular capacitance in man and animals are then discussed. The last part focuses on the reflex control of the circulation in man.
LanguageEnglish
Release dateMar 28, 2014
ISBN9781483155616
Cardiovascular Physiology Neural Control Mechanisms: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980

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    Cardiovascular Physiology Neural Control Mechanisms - A. G. B. Kovách

    Sciences

    INTEGRATIVE ROLE OF THE CENTRAL NERVOUS SYSTEM IN CARDIOVASCULAR CONTROL

    P.I. Korner,     Baker Medical Research Institute, Melbourne, Australia 3181

    Publisher Summary

    Circulation is a hydraulic regulator in which the heart adjusts cardiac output through intrinsic mechanisms determined by cardiac filling, afterload and inotropic state. In the peripheral circulation, the local autoregulatory properties of the regional beds adjust blood flow to each organ’s metabolic needs. This chapter illustrates a flow diagram that shows the major components of the circulatory control system. An optimum operation of CNS autonomic mechanisms involves a large number of integrations through neuron groups that are widely distributed from cortex to spinal cord. Noradrenergic and serotonergic neurons are a part of the network, but there are probably many other types of transmitters involved in the autonomic pathways. Anesthesia often distorts the integrative capacity of the CNS. During environmental disturbances, there are often changes in many peripheral receptors. Interactions that alter the properties of the arterial baroreflex have particular homeostatic importance as they can greatly alter the capacity of the body to correct for large circulatory perturbations.

    Introduction

    The circulation is a hydraulic regulator in which the heart adjusts cardiac output through intrinsic mechanisms determined by cardiac filling, afterload and inotropic state. In the peripheral circulation, the local ‘autoregulatory’ properties of the regional beds adjust blood flow to each organ’s metabolic needs. The flow diagram in Fig. 1 shows the components of this system important in overall circulatory control. A disturbance through its direct local effects on heart and vasculature will produce changes in arterial, cardiac and pulmonary pressures which are signalled to the CNS through the different groups of baroreceptors. This information together with changes in many other sensory modalities activates many regions in the CNS. The important difference of the closed-loop operation of this control system is the variety of sensory information it receives, contrasting with the classic open-loop analysis of cardiovascular reflexes where the activity of all inputs except that under study are maintained onstant or eliminated (1). The information reaching the CNS evokes a pattern of autonomic effector activity that is characteristic for the particular stimulus profile. These autonomic effects together with the direct local effects of the disturbance determine the final circulatory response.

    Fig. 1 Major components of circulatory control system.

    Autonomic activity may also be initiated by the CNS instead of being evoked primarily from peripherally determined information. Highly characteristic autonomic patterns may be part of a voluntary motor act or can occur, in association with different types of behaviour (2). In the event, each type of autonomic response in the intact organism is determined by both reflex and behavioural factors. Thus disturbances starting primarily owing to changes in activity in peripheral receptors also alter behaviour which may modify the autonomic response (3). In turn changes in autonomic activity initiated by central ‘command’ will alter intravascular pressures and the activity of peripheral receptors which will again influence the autonomic response (2,3).

    In this lecture I have limited discussion to integrations of autonomic responses evoked primarily from peripherally determined inputs, mainly because they are more readily subjected to quantitative study than behaviourally determined changes in autonomic function. The first part of the lecture considers the major design features of the CNS autonomic pathways. Even the simplest autonomic response is mediated through numerous integrative sites. Furthermore, the sympathetic nervous system is not just a system for uniform mass action, as was at one time envisaged by Cannon (4). Instead, its activity is often non-uniform, with an increase in some outflows and a decrease in others. Another aspect briefly considered is the number of different chemical transmitters linking the various components of the autonomic network (e.g. noradrenergic and serotonergic neurons). Parenthetically, anaesthesia can distort considerably the normal operation of this system.

    The second part of the lecture considers the special problems of input-autonomic output relationships in the intact organism where the CNS is presented with a complex input profile. The autonomic responses frequently appear anomalous and are difficult to predict from classic reflex analysis as the sum of the individual reflex effects. Such non-linear behaviour is often due to interactions in the CNS and its main feature is that a given autonomic response to unit change in one input becomes markedly altered by the level of activity in one or more of the other inputs. Examples considered here are chemoreceptor-ventilatory interactions and CNS ‘resetting’ of arterial baroreceptor reflex properties. The latter can greatly modify the capacity of the circulatory control system to cope with environmental disturbances.

    Organisation of CNS Autonomic Pathways

    Up till 1960’s the classic cardiovascular centres of the pons and medulla were considered to have a very dominant role in the integration of reflex responses, including those arising from the arterial baroreceptors, chemoreceptors and visceral and somatic afferents (5). Brain regions such as the hypothalamus, limbic system and cortex were considered to play a role only in special regulatory tasks, e.g. exercise, temperature regulation and behaviour.

    The current view considers that in the conscious intact animal, as far as we know, every type of autonomic response occurs through numerous integrations involving many parts of the brain (Fig. 2). Inputs from the heart and blood vessels reach the CNS through IX and X. cranial nerves and through spinal sympathetic afferents. They synapse to project to widely distributed integrative sites from which they project to the various autonomic motoneuron pools. There are thus elaborate connections longitudinally throughout the brain as well as links between different neuron groups at any particular level. Clearly in several of the suprapontine sites information from peripheral receptor groups must come into close contact with projections from mechanisms subserving central ‘command’.

    Fig. 2 Organisation of CNS autonomic pathways

    There is thus a great deal of divergence and convergence of information, so that (i) a given input projects to numerous integrative sites in different parts of the brain (6); and (ii) a given group of autonomic motoneurons receives axons from any integrative sites (7).

    With the wide distribution of neuron groups throughout the CNS it is important not to overemphasize the hierarchic nature of the different integrative sites by calling them ‘higher’ or ‘lower’ centres. The network is one allowing multiple access of information at numerous levels and has many outputs. Integrations performed by bulbo-spinal mechanisms such as the tractus solitarius and its nucleus, or by the autonomic interneurons of the spinal cord appear to be amongst the most complex of the autonomic network (3).

    We do not yet know enough about the anatomical connections or the exact functions of the various integrative sites. Indeed, in many disturbances we are far from clear which the various neuron groups are that contribute to production of a particular autonomic response. It is for this reason that input-output analysis is still such an important tool of analysing the properties of the control system.

    Examples of Integrative Activity

    The various components that comprise the CNS autonomic pathway have both an ‘amplifier’ function where more volume is provided and fine ‘tuning’ function that helps to adjust the autonomic response to the particular stimulus. The suprapontine components of the network allow integration of information that overlaps but is not identical with that reaching bulbar or spinal mechanisms, but is no more important in the overall response.

    Tonic Activity

    In pontine decerebrate preparations arterial pressure is the same as in animals with intact CNS, but heart rates are lower (8). Uther et al (8) found that this was due to similar attenuation of both vagal and sympathetic effects on heart rate (Fig. 3) and not to a preponderance of vagal activity as had been thought (9). This is an example where additional components of the network simply provide additional amplification.

    Fig. 3 Tonic effects on heart rate mediated through vagus and sympathetic in intact and pontine rabbits; ‘intrinsic’ heart rate after autonomic block was the same in both groups (8)

    Baroreceptor Reflexes

    Decerebrate animals have functioning arterial baroreflexes which differ mainly quantitatively from those of intact animals. For example, Kent et al (10) studied the effects on systemic blood pressure of altering the pressure in the isolated carotid sinus in anaesthetised vagotomised cats. After decerebration the range of the systemic blood pressure response to the maximum changes in sinus pressure was reduced (Fig. 4, left). In another study we found that baroreceptor-heart rate reflex properties were quantitatively different in unanaesthetised rabbits with intact CNS from those of thalamic and pontine preparations. Sigmoid function curves were derived relating mean arterial pressure (MAP) to heart period (HP, pulse interval) by briefly raising and lowering blood pressure above resting by inflating balloons placed around the aorta and vena cava. The main differences between preparations were in reflex gain (sensitivity) threshold for evoking bradycardia and in median blood pressure (BP50; blood pressure at midpoint of HP range) (11). In a more recent study in another strain of rabbits we found an even greater decrease in gain in pontine rabbits and on this occasion HP range was also reduced (Fig. 4, right)(12).

    Fig. 4 Effect of decerebration of baroreflexes in anaesthetised cat (left; 10) and unanaesthetised rabbit (right; 12)

    In relation to the baroreceptor-heart rate reflex fine ‘tuning’ is provided by effects mediated through central noradrenergic neurons and serotonergic neurons. The functions of these transmitters can be demonstrated by studying the acute and chronic effects observed after intracisternal injection of the selective neurotoxins 6-hydroxydopamine (6-OHDA) or 5,6-dihydroxytryptamine (5,6-DHT). With these drugs many of the circulatory changes observed over the first few hours after injection are due to release of noradrenaline (after 6-OHDA) or serotonin (after 5,6-DHT)(12,13) and can be blocked respectively by phentolamine and methysergide (14,15). Increased noradrenaline release after 6-OHDA greatly enhances HP range and gain. Only the upper plateau of the MAP-HP curve is affected, suggesting that there is facilitation mainly of cardiac vagal motoneurons (Fig. 5(11,16). Enhanced serotonin release after 5,6-DHT elicits the opposite changes in HP range and gain, though as with noradrenaline release there is an increase in BP50. Thus the control of HP range and gain of vagal motoneurons is mediated partly through the antagonistic actions of bulbar noradrenergic and serotonergic neurons (15). This can be regarded as baroreflex control through parallel pathways which provide central vagal motoneurons with a dual innervation analogous to that of the heart. On the other hand control of BP50 and threshold are mediated through a pathway whereby bulbar serotonergic neurons synapse with noradrenergic neurons to reach suprapontine brain regions before returning to the medulla (15). This arrangement to two types of monoaminergic neurons arranged in series is analogous to the different types of neurons involved in ganglionic transmission.

    Fig. 5 Changes in curves relating mean arterial pressure (MAP) to heart period (HP, pulse interval) before, and 2 and 4 hours after intracisternal 6-OHDA (left) and 5,6-DHT (right), showing effects of synaptic release of noradrenaline and serotonin (12,15)

    We do not know which are the exact noradrenergic or serotonergic neuron groups involved in the above responses. However, we do know that destruction of either noradrenergic and serotonergic pathways produces chronic changes in baroreceptor-heart rate reflex properties due to unmasking of the tonic activity of the remaining transmitter system.

    Anaesthesia

    Anaesthetics have complex depressant effects on the CNS. Vagal efferent mechanisms are particularly susceptible (3). We have found differences in depression produced by different agents in a study which compared the effects of althesin (a new steroid agent), ketamine (an anaesthetic used in hypotensive states) and thiopentone (a barbiturate) on the MAP-HP curves of the baroreceptor-heart rate reflex (17). The effect of each drug was compared in the same rabbit on different days using similar levels of very light anaesthesia. With every anaesthetic there was depression of the upper MAP-HP curve plateau (Fig. 6). The order of depression was althesin

    Fig. 6 Effects of infusions of althesin (A) ketamine (K) and thiopentone (T) and dextrose (D, control without anaesthesia) on baroreceptor-heart rate reflex properties in the rabbit (17)

    Certain responses such as the nasopharyngeal reflex or the diving response can become profoundly altered by relatively mild vagal depression. These responses depend for their oxygen conserving effect on a marked rise in vagal activity which greatly reduces cardiac output so that, in conjunction with increased sympathetic constrictor activity, there is marked reduction of peripheral blood flow (18). If there is vagal depression cardiac output will not be reduced sufficiently to help to greatly lower regional blood flows, even if there is the same rise in constrictor activity as before. Under these conditions there is more rapid utilization of available oxygen supply, inappropriate to the emergency needs of the animal.

    Anaesthetics thus distort the capacity of the CNS autonomic pathways for performing complex integrative acts. This is why any analysis should ideally use at least some results from unanaesthetised preparations if at all possible.

    ‘Cost-Benefit’ of Autonomic Patterns

    in unanaesthetised rabbits comparing the responses of intact, thalamic and pontine animals. In each group the magnitude of the neural effects and those of the adrenal catecholamines and the direct local effects of hypoxia were assessed (8,19,20). The local effects at this level of hypoxia consisted mainly of vasodilatation which varied in magnitude in the different regional beds in the order portal>renal>muscle>skin beds (Fig. 7).

    Fig. 7 Local effects (open rectangles), neural (black) and adrenal catecholamine (hatched) effects on heart rate and regional vascular resistances in different preparations during severe arterial hypoxia. (+) = increase in rate or resistance; (-) = decrease in above (8,2223–24)

    In intact rabbits the fall in heart rate was due to the synergistic action of increased vagal activity and reduced sympathetic activity (Fig. 7). The activity of the sympathetic constrictor nerves to portal, renal and muscle vascular beds all increased; by contrast there was inhibition of constrictor tone in the ear skin bed. The adrenal catecholamines reinforced the neural sympathetic vasoconstriction of portal and renal beds presumably through synergistic action on α-adrenoceptors (8). However, in the skeletal muscle bed β-adrenoceptors on the resistance vessels are of functional importance. These were stimulated by reflexly secreted adrenaline and masked the neurally mediated α-constrictor effects (8,21) producing a net vasodilatation.

    In thalamic rabbits the pattern of vagal and cardiac sympathetic effects on heart rate was the same as in intact rabbits (Fig. 7). The neural constrictor effects in portal, renal and muscle outflows were all enhanced but adrenal catecholamine secretion during hypoxia was reduced or absent, accounting for the particularly pronounced constrictor response in the skeletal muscle bed. In the ear bed sympathetic constrictor tone was again inhibited.

    There were thus considerable similarities in autonomic response patterns between intact and thalamic rabbits. By contrast in pontine rabbits there was a gradual increase in heart rate, which was largely sympathetically mediated (Fig. 7). Neural elevation in constrictor activity was prominent only in the portal bed and was not detectable in kidney and muscle, but in the skin bed there was slight vasoconstriction instead of inhibition as in the other preparations. The estimated secretion of adrenal catecholamines was enhanced.

    The pattern of sympathetic neural activity in normal rabbits was thus non-uniform, increasing in some outflows and decreasing in others. This differentiation of pattern depended on the integrity of hypothalamic mechanisms. In the overall autonomic response catecholamine secretion was important in influencing the circulatory changes, as was the non-uniform local hypoxic vasodilatation.

    The ‘cost’ to the organism of the three different types of circulatory control can be assessed from the time-dependent pH changes. The different preparations develop slight acidosis which does not occur in adrenalectomised, or propranolol treated rabbits, or in animals without functioning autonomic effectors, which develop the usual respiratory alkalosis (Fig. 8). Hence the acidosis depends entirely on autonomic factors and provides a measure of the metabolic cost in in the different preparations. The fall in pH was in the order pontine>thalamic>intact rabbits (8,20).

    Fig. 8 Changes from control after 35 min hypoxia in sham-operated, thalamic and pontine rabbits in pH (upper) and MAP (lower) in intact, adrenalectomised, propranolol treated and ‘de-efferented’ rabbits

    The capacity to maintain arterial pressure during severe arterial hypoxia can be used as an indicator of ‘success’ of a particular autonomic control system. On this simple criterion all three preparations were ‘successful’, at least over the first 20-30 minutes of the disturbance. Later on the greater H+ ion production in pontine rabbits probably resulted in the slightly greater late fall in blood pressure in this group (Fig. 8).

    These preparations provide models of the fine tuning performed by numerous regions of the CNS in adjusting the organism’s autonomic responses to a range of input signals. Perhaps the most important illustration in these experiments is that intense prolonged autonomic responses exact a metabolic toll from the organism.

    Interactions and Non-linearities

    When there is simultaneous activation of two sets of inputs A and B the evoked net response is often due to simple summation A′+B′, where the latter are the individual open-loop responses obtained by altering each input under controlled conditions (1). In other instances stimulating (A + B) evokes the non-linear response A′ + B′ + A′B′, where the last term is an interaction term. The latter indicates that the response to one input is markedly influenced by the activity in the other input. Examples of non-linear CNS interactions considered below are those involving cardio-respiratory interactions in arterial hypoxia and CNS mechanisms of ‘resetting’ of arterial baroreflex properties.

    Chemoreceptor-Ventilatory Interactions

    The first example considered relates to gradation consists of tachycardia and a slight rise in autonomic component of TPR (. The bradycardia was even more marked in thalamic rabbits. Transection behind the hypothalamus abolished the response (22). In pontine rabbits there was a rise in heart rate of gradual onset related to the severity of hypoxia (Fig. 9).

    Fig. 9 Autonomic time-related heart rate effects in four neurological preparations of unanaesthetised rabbits before, during (arrows) and after 45 min of arterial hypoxia (22)

    of about 35 mmHg and with more severe arterial hypoxia ventilation stays steady or declines (below 35 mmHg lung inflation receptor activity tends to decline whilst that from the chemoreceptors rises dramatically resulting in a fall in input ratio. In the rabbit these afferent changes appear to be sampled by different integrative sites in cortex and hypothalamus. When the lung inflation/chemoreceptor input ratio is large during mild hypoxia cortical influences suppress the bradycardia mediated through the hypothalamus, and the bulbo-spinally mediated rise in heart rate becomes manifest (Fig. 9). When the input ratio declines during more severe hypoxia, the diencephalically-mediated bradycardia becomes increasingly evident. Similar differences in TPR responses occur in the different suprapontine preparation (22). The magnitude of the autonomic heart rate and TPR responses is thus determined by a simple ‘comparator’ mechanism of the magnitude of lung inflation and chemoreceptor inputs.

    relationship to the rabbit, but always a rise in heart rate even with very severe hypoxia (Fig. 10)(25). We were fortunate to have Professor Michael de Burgh Daly help us sort out the chemoreceptor responses in the anaesthetised monkey (28,29). Strong stimulation of the isolated arterial chemoreceptors with hypoxic blood or with cyanide or CO2 generally evokes a rise in heart rate, or only slight transient slowing of 1-2 beats (Fig. 11). This still occurs after controlling ventilation. Only when the central respiratory mechanisms are inhibited completely, either by stimulating the superior laryngeal nerve or by stimulating the nasopharynx, is there pronounced bradycardia and vasoconstriction during subsequent chemoreceptor stimulation (Fig. 11).

    Fig. 10 Effects of moderate and severe arterial hypoxia on ventilation, MAP and heart rate (HR) in unanaesthetised monkey and rabbit (25,26)

    Fig. 11 Changes from above, in phasic and mean femoral artery blood flow, blood pressure, inferior vena cava pressure and tidal volume. A. Injection of NaCN into carotid artery (arrow). B. Bar indicates nasopharyngeal stimulation; arrow denotes NaCN injection (29)

    In the spontaneously breathing dog and cat hypoxia normally elicits autonomic responses similar to those of the monkey (30). However, with controlled ventilation or after section of the pulmonary vagi, arterial chemoreceptot stimulation evokes reflex bradycardia and vasoconstriction (30).

    Thus in all the above species chemoreceptor stimulation can elicit bradycardia and vasoconstriction. But the circumstances differ in the various species. In the rabbit the major factor determining whether bradycardia and vasoconstriction become apparent during arterial hypoxia is the lung inflation/chemoreceptor input ration and the role of the respiratory ‘oscillator’ appears relatively unimportant. In the dog ventilation must be controlled close to resting or input from lung inflation afferents eliminated before the above responses are evoked. In the monkey they occur only after complete inhibition of CNS respiratory ‘oscillator’; lung inflation afferents appear less important than in the subprimates. In the primate species the O2-conserving function of the chemoreceptor-circulatory reflex only comes into play as the absolutely last line of the body’s defence. Escape from the hypoxic environment is probably better for the primate’s sophisticated CNS than the oxygen conservation mechanisms developed in burrowing and diving species.

    Significance of Arterial Baroreflex ‘Resetting’

    There are now numerous studies from many laboratories showing that non-linear CNS interaction can alter the various autonomic responses to arterial pressure changes (see ref.3). Such changes in baroreflex properties can occur owing to interactions in the CNS between arterial baroreceptor pathways with inputs from other peripheral receptors, or with central ‘command’ mechanisms (e.g.31). The first type of arterial baroreflex ‘resetting’ (e.g. in arterial hypoxia) has non-uniform effects on the different sympathetic neural outflows (Fig. 12)(3,23,22). Thus during hypoxia there was an increase from its control value in renal sympathetic baroreflex gain, sympathetic activity range and in BP50, but in the cardiac sympathetic baroreflex these parameters decreased. After decerebration ‘resetting’ during hypoxia was abolished in both outflows, suggesting that it was normally mediated through suprapontine integrative sites (23). ‘Resetting’ involved interactions mainly between chemoreceptor and arterial baroreceptor inputs. However, splanchnic sympathetic baroreflex properties were not ‘reset’ during arterial hypoxia. The ear sympathetic outflow is an example of a constrictor outflow that is not affected by the arterial baroreflex but, as discussed earlier, is inhibited by increased chemoreceptor activity in arterial hypoxia

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