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Central Adrenaline Neurons: Basic Aspects and Their Role in Cardiovascular Functions
Central Adrenaline Neurons: Basic Aspects and Their Role in Cardiovascular Functions
Central Adrenaline Neurons: Basic Aspects and Their Role in Cardiovascular Functions
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Central Adrenaline Neurons: Basic Aspects and Their Role in Cardiovascular Functions

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Central Adrenaline Neurons: Basic Aspects and their Role in Cardiovascular Functions contains the proceedings of an international symposium held at The Wenner-Oren Center, Stockholm on August 27-28, 1979. The purpose of the meeting is to summarize the knowledge of central adrenaline neurons and their role in cardiovascular functions. Organized into four sections, this book begins with a discussion on the morphology, biochemistry, and pharmacology of central adrenaline neurons. Subsequent sections detail the cardiovascular functions of central catecholamine neurons and the effects of centrally acting drugs on sympathetic function in normotensive and hypertensive patients. An overview lecture of the concept of a- and ß-adrenergic receptors is also shown.
LanguageEnglish
Release dateOct 22, 2013
ISBN9781483154695
Central Adrenaline Neurons: Basic Aspects and Their Role in Cardiovascular Functions

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    Central Adrenaline Neurons - Kjell Fuxe

    Sweden

    OPENING ADDRESS

    B. HÖKFELT,     Department of Endocrinology, Lund University Clinics, S-214 01 Malmö, Sweden

    The purpose of this symposium is to summarize and further advance our knowledge about the distribution and functional role of the adrenaline neurons within the central nervous system. This area is comparatively new in the sense that it is only during the last decade that we have begun to trace the role of the adrenaline neurons in the very complex central machinery.

    The term adrenaline - like that of epinephrine - of course refers to its presence in the adrenal and as such its location near to the kidney. In 1895, Oliver and Schaefer for the first time demonstrated the pronounced blood pressure-raising property of intravenously injected adrenal medullar extracts, thus demonstrating for the first time the hormonal activity of this gland. Using the blood pressure response as a method of assay, the essential active principle of the adrenal medulla was purified by Abel and then isolated by Takamine in 1901. He designated it adrenaline and it was the first of the natural hormones to be isolated. A few years later it also became the first synthesized hormone (Stolz 1904).

    The importance of the suprarenal glands for the maintenance of life was originally documented by Thomas Addison, a London physician, in 1855, when he for the first time linked atrophy or destruction of the adrenal glands with the life threatening manifestations of adrenal cortical insufficiency. Inspired by Addison’s description Brown-Séquard (1856) and others tried to reproduce the disturbance experimentally in various animal species by the extirpation of the adrenals. Uniformly, bilateral adrenectomy rather rapidly ended in death and it was rightly concluded that the presence of the adrenals is necessary for survival. The discovery of adrenaline initially lead some people to believe that they now had in their hand the factor, whereby the adrenals exert their life saving functions. However, it soon became evident that this was not the case and that the vital function of the adrenal refers to the adrenal cortex rather than the medulla.

    At the very beginning of this century Lewandowsky and Langley independently pointed out the striking similarity between the response to stimulation of the sympathetic nerves to an organ and the reaction in the corresponding organ to the injection of suprarenal gland extract. It was thus not surprising that Elliott, the first proponent of the idea of neuro-humoral transmission, presented the view that the transmitter substance liberated at sympathetic nerve endings was adrenaline (1904). Although several investigators during the following years expressed doubts upon the theory of adrenaline as the sympathetic transmittor, it was not until 40 years later that Ulf von Euler brought convincing evidence that noradrenaline fulfils this function.

    It was, however, quite clear that extracts made from organs densely innervated by sympathetic nerves - such as the heart and the spleen - in addition to noradrenaline also contains minor amounts of adrenaline. This was for a long time difficult to explain but was solved in the 50th, when it became clear that circulating adrenaline like noradrenaline can be taken up by the sympathetic nerve endings and stored there.

    With respect to central neurotransmission, Marthe Vogt in 1954 showed that noradrenaline is present in high concentrations in the mammalian hypothalamus and to some extent in other parts of the brain. Evidence was also presented by Carlsson for the presence of dopamine within the central nervous system. These discoveries constituted that background for the fascinating development during the last two decades concerning the functional role of these amines, such as their involvement in the regulation of hypothalamic-pituitary function and cardiovascular mechanisms. This development was to a great extent made possible by the introduction of the nowadays well-known and widely applied histochemical procedure by Faclk and Hillarp in 1962.

    To return to adrenaline, both Holtz (1950) and Marthe Vogt (1954) presented evidence for its presence in the central nervous system but more definite proof was produced by Gunne in von Euler’s laboratories in 1962. However, it was not until rather recently, that more detailed informations about its location and possible functions was reached. This had to await further methodological developments in terms of histochemistry, immunohistofluorescence and high pressure liquid chromatography and the application of these procedures in combination with specific inhibitors of catecholamine synthesis and drugs interfering with sympathetic transmission.

    Progress has been fast and exciting and has lead to the belief that adrenaline neurons are involved in the normal regulation of cardiovascular and respiratory functions and perhaps also play a primary or secondary role in the development of hypertension. Indeed, in its way the history of adrenaline is somewhat remarkable. It was identified some 85 years ago in the adrenal medulla where it is present in milligram quantities but seems to play no major, if any physiological role. In the brain, on the other hand, adrenaline is present in minute quantities only but seems to serve as an essential link in important regulatory functions. Further research in this area is essential from a physiological point of view but also with respect to disease mechanisms and for the development of new therapeutic agents.

    Section I

    THE MORPHOLOGY AND BIOCHEMISTRY OF CENTRAL ADRENALINE NEURONS

    THE ANATOMY OF CENTRAL CARDIOVASCULAR NEURONS

    M. PALKOVITS,     First Department of Anatomy, Semmelweis University Medical School, Budapest, H-1450, Hungary

    Publisher Summary

    Central neuronal regulation of the cardiovascular mechanisms is rather complex. This chapter provides an overview of the anatomy of the central cardiovascular neurons. It discusses the elements of the cardiovascular reflex arc. The peripheral pathway of the cardiovascular reflex arc originates in the stretch receptors. Although the neurons of the cardiovascular modulatory centers and the efferent neurons of the cardiovascular reflex arc are centrally located, the term central cardiovascular neurons means only those neurons that belong to the nucleus of the solitary tract as it is the main organizing center of the reflex arc. The nucleus of the solitary tract (NST) serves as a relay station in the cardiovascular reflex arc. Its efferent fibers are projected to various brain regions to involve them in the cardiovascular modulatory mechanisms. The efferent fibers can be grouped as follows: (1) efferent cardiovascular neurons, (2) higher cardiovascular modulatory centers, and (3) brain stem nuclei. Efferent neurons in the medulla and the spinal cord represent the third component of the cardiovascular reflex arc.

    Central neuronal regulation of the cardiovascular mechanisms seems to be rather complex. Several neuronal structures are primary or secondary involved. Using the classical neuroanatomical description - to start from the periphery and to return there studying the individual components of the cardiovascular reflex arc in between -looks reasonable to investigate and to understand these structures.

    ANATOMY OP THE CARDIOVASCULAR REFLEX ARC

    Elements of the cardiovascular reflex arc are summarized in Fig. 1. and Table 1. They have been detailed earlier (Refs 28,30). The peripheral pathway of the reflex arc originates in the stretch receptors (carotid sinus, aortic arc, cardiac wall). The perikaryon is a pseudounipolar cell in the superior or inferior ganglia having a central process to terminate in the medulla oblongata, in the nucleus of the solitary tract (NST). This is the first or afferent neuron of the reflex arc.

    TABLE 1

    Components of the Baroreceptor Reflex Arc

    1. AFFERENT CARDIOVASCULAR NEURON

    (From the periphery to the nucleus of the solitary tract) Cell bodies: nodose ganglion

    2. CENTRAL CARDIOVASCULAR NEURON

    Cell bodies: nucleus of the solitary tract

    a. Axons to the efferent cardiovascular neurons

    b. Axons to the modulatory centers, from where

    c. Axons back to the efferent neurons

    3. EFFERENT CARDIOVASCULAR NEURON

    (From the medulla or spinal cord to the periphery) Cell bodies:

    a. Preganglional nucleus: dorsal vagal nucleus intermediolateral nucleus

    b. Postganglional nucleus: vegetative (vagal and sympathetic) peripheral ganglia

    Fig. 1 Cardiovascular reflex arc

    Perikarya in the area of the NST seem to be the second or central neurons having more different projection possibilities. There is a simple or short reflex directly to the efferent neurons (2a in Fig. 1 and Table 1) connecting the NST with the periphery without involving higher centers in the reflex mechanisms. Such short loop reflexes are generally believed to belong to the vegetative nervous system. Ascending axons from the NST to higher cardiovascular modulatory centers represent the other type of the baroreceptor output (2b in Fig. 1. and Table 1). Our knowledge concerning their topography, termination and chemical character is going to be summarized later on. Axons from higher cardiovascular modulatory centers descend to terminate on the efferent neurons (2c in Fig. 1 and Table 1). Accordingly, the origin and the termination of the long loop and the short loop is the same, but higher modulatory centers are inserted between the afferent and efferent pathways in the former establishing the anatomical basis of a wide range modulation in the cardiovascular mechanisms. Consequently, neuronal structures involved in the cardiovascular regulation (hypothalamus, limbic system, midbrain-pontine cellgroups) receive the neural cardiovascular information only through the NST so exerting their effects indirectly, over the efferent neurons.

    The efferent neurons form the third component of the cardiovascular reflex arc. These cells are located in the medulla oblongata and the spinal cord and their axons leave in the vagal nerve or in the spinal sympathetic nerve to reach the periphery (3a in Fig. 1 and Table 1). They are presynaptic neurons as before reaching the periphery have a with-over in the vegetative ganglia (vagal, sympathic, cardiac). Hence this last part of the reflex arc consists of post-ganglionary fibers (3b in Fig. 1 and Table 1).

    TOPOGRAPHY OF THE CENTRAL CARDIOVASCULAR CELLS

    Although the neurons of the cardiovascular modulatory centers as well as the efferent neurons of the cardiovascular reflex arc are centrally located, the term central cardiovascular neurons means only those belonging to the nucleus of the solitary tract, being the main organizing center of the reflex arc.

    Topography and Subdivisions of the Nucleus of the Solitary Tract

    Detailed descriptive anatomy of the nucleus is well known (Ref.28). It has a role in more different functions (cardiovascular, gustatory, respiratory) and receives neural input through several cranial nerves (trigeminal, facial, glossopharyngeal and vagal). The nucleus extends over almost the whole length of the medulla oblongata. At the beginning it is deeply and laterally located. Caudally, it gets closer to the basal surface of the medial part of the IVth ventricle. At the level of the obex, the left and right part keeps on closing to each other and finally after being fused the cells form the nucleus commissuralis in the midline until the beginning of the spinal cord (28).

    Cardiovascular neurons represent only a part of the NST. The rostral part has been implicated as regulating the gustatory functions while the lateral participates in the respiratory functions.

    The medial part in itself does not even seem to be homogeneous concerning its neuronal pattern, as more subdivisions in more species have been separated (20,25) only some of them having a role in cardiovascular regulation. Cells of the medial part immediately before, at and after the obex level seem to be connected to the blood pressure regulation. Lesioning this area resulted in an elevation of the blood pressure and microinjection of noradrenaline into this area caused a decrease, while the same interventions some 0,1 mm further failed to induce any change in blood pressure (18,19,49). This area contains only the terminations of the vagal nerve. How much and to what extent the pars commissuralis - where the vagal fibres running caudally in the solitary tract terminate both ipsi-and contralaterally - participates in the central regulation of blood pressure is still a question.

    Quantitative Parameters of the Nucleus of the Solitary Tract

    The area occupied by the NST is relative small, not more than 3-4% of the whole medulla. However, because of the particularly high cell density, a significant number of the medullary cell population is located here. Having a cell density of 37.000/mm³ it belongs to the relatively dense areas in the CNS (Table 2). Among its different parts, the medial is the biggest constituting 59% of the whole nuclear volume. Topographically, 0,384 mm³ (58%) is before and 0,273 mm³ (42%) is beyond the obex level. The number of neurons in the medial part is 27.350 (64% of the total NST population (Table 2). The area likely to be involved in the cardiovascular regulation (from 0,6 mm rostral to the obex to 0,5 mm caudal to it) has 20.000 neurons on the average. This number should be considered to be the upper limit, as all cells - even which have nothing to do with the cardiovascular regulation - are included. On the other hand a part of the pars commissuralis neurons (7000 cells) is certainly involved in the blood pressure regulation, too.

    TABLE 2

    Volume, Cell Density and Numbers of the Nucleus of the Solitary Tract and the Dorsal Vagal Nucleus (n = 4-8)

    There are no exact data available on the number and density of synaptic terminals within the NST. Chiba and Kato (3) calculated 2000 presynaptic profiles in a 6800 μ² surface area. Knowing the size of the presynaptic boutons our preliminary calculations suggest the number of terminals per one neuron is between 1000-2000. This means that there are about 20-30 million nerve terminals on the 20.000 neurons of the medial NST part playing an important role in the cardiovascular regulation. We have no quantitative data on the origin of all these terminals.

    On the Chemical Character of the NST Neurons

    Nothing is known about the chemical character of the majority of these neurons. Different cell types were described in the last years in the NST and its vicinity using histofluorescence and immunofluorescence methods (Table 3).

    TABLE 3

    Neurotransmitters and Neuronal Peptides in the Nucleus of the Solitary Tract

    (numbers) = references

    It is known since the description of Dahlström and Fuxe (7) that noradrenaline containing cells are scattered in the NST caudally to the obex (including the pars commissuralis) and in the area of the dorsal vagal nucleus (DVN). This group of cells is called A2 cellgroup. There are no exact quantitative data on this area. According to Swanson and Hartman (41) the number of A2 cells is about the one fourth of the locus coeruleus cell number. That means, there are around 1000 neurons here, which is not more, than 3% of the total NST cell number, and 5% of those cells participating in the cardiovascular regulation.

    Phenylethanol N-methyl-transferase (PNMT) immunoreactive adrenaline containing cells were described by Hökfelt et al. (15) in the rostral part of the NST, respectively in its close vicinity under the medial part of the IVth ventricle (Cl-cellgroup). Their number seems to be much less than the noradrenaline containing cells. Enkephalin (14,17,43), substance P (13) and neurotensin containing cell bodies were also described in the NST region by immunocytochemistry. Enkephalin and neurotensin containing cells are restricted to the medial part, while those containing substance P can be detected in the medial part as well as in the pars commissuralis. No data are available concerning their number, however, it is not likely to exceed hundreds, as an order of magnitude. Whether a certain neuron contains only one certain neuropeptide or there is a coexistence in one cell, is not yet known.

    Other neurotransmitters and neuropeptides detectable by known specific reactions could not be demonstrated in the NST perikarya. This way, the character of the great majority of the NST neurons is still unknown.

    Neuronal Afferents to the Nucleus of the Solitary Tract

    The neuronal input to the NST can be listed as: 1. afferents from the cranial nerves; 2. axons from the hypothalamus; 3. catecholamine nerves and 4. others.

    ad 1. The sensory axons of the Vth, VIIth, IXth and Xth cranial nerves terminate in the NST (ref.28). Among these only those of the vagal nerve terminate in the area of the pars medialis involved in cardiovascular regulation and in the pars commissuralis. These fibres are the central processes of neurons located in the jugulary (superior) and the nodose (inferior) ganglia (l). Fibers descend in the solitary tract until the lower part of the pars commissuralis. Mainly caudally, a part of the fibers decussate (1,20 and Ref.30). Fibers divide within the NST, form a network and have termination at the same time in adjacent regions like the area postrema, dorsal motor vagal nucleus, nucleus intercalatus and in the parvicellular reticular formation immediately neighbouring the NST (1 and Ref.28). The peripheral input amounts to only a small part of the NST nerve terminals, to just 15% according to Chiba and Kato (3). The rest comes from other afferents and intranuclear connections. The chemical character of the cardiovascular vagus fibres is still not known.

    ad 2. Several hypothalamic nuclei are in direct monosynaptic contact with the cells of the NST. Different morphological methods seem to be adequate to study these connections (autoradiography, retrograde tracing techniques). Table 4 is to summarize the origin of the NST afferents. Some of the descending fibres originating in the paraventricular and suprachiasmatic nuclei contain vasopressin and neurophysin (38,39,40) but the chemical character of all the others is not yet known.

    TABLE 4

    Afferent and Efferent Neuronal Connections of the Nucleus of the Solitary Tract

    AU - autoradiography

    HRP - horseradish peroxidase

    EM - electron microscopy

    IM - immunocytochemistry

    ad 3. The catecholamine innervation of the NST is rather rich, the concentrations of noradrenaline, dopamine (46) and adrenaline (12) are the highest in the medulla. Besides the noradrenaline and adrenaline containing perikarya in the nucleus itself and in the adjacent regions a very rich adrenergic network (15,23) and terminals could be demonstrated. The majority of them is of local origin (i.e, A2 and C2 cells), but other noradrenergic cellgroups provide contribution, too. The locus coeruleus seems to be the most important among those, having a bidirectional connection with the NST region (24,42). These connections have been proved by many different methods (Table 4).

    ad 4. More different nerve terminals have been shown in the NST (see below and Table 3). Their origin is not yet known. They may either be of cortical, brain stem or spinal cord origin (ref.28) or intranuclear (probably belonging to local substance P, neurotensin and enkephalin neurons).

    Humoral Afferents to the Nucleus of the Solitary Tract

    Not only the neuronal but the humoral inputs to the NST could have role in the central cardiovascular regulation. The NST is supplied by the branches of the vertebral and basilar arteries. The end branches reach the nucleus both from dorsal and ventral direction to form a dense capillary network there which is characteristic to the medullary regions. As the capillaries are not known to be fenestrated the existence of the blood brain barrier in the NTS region has to be taken into account. Nevertheless, the NST has a privileged position with respect to the humoral input. The explanation is its close topographical, vascular and neural connection with the area postrema. The area postrema, practically lacking all kinds of barriers, starts at the obex level in the rat and is quasi embedded in the medial part of the NST. The organ - being a typicalcircumventricular organ - is highly vascularized. Using indian ink perfusion branches from this region can be followed into the NST. On the other hand, using the Golgi impregnation method, several dendrites of NST neurones can be traced into the area postrema region. The close topographical connection of the area postrema with the ventricular system (situated at the caudal corner of the IVth ventricle above the origin of the central canal) enables the transport of substances present in the cerebrospinal fluid to the direction of the NST. Earlier the area postrema in itself was supposed to have some role in the blood pressure regulation. Later it was shown that the removal of the organ failed to cause hypertension (48). Still, it remained possible to involved in the transport of certain cardiovascular inputs.

    Chemistry of Nerve Terminals in the Nucleus of the Solitary Tract

    As is shown by the results of the quantitative studies there are numerous terminals in the NST. With the refinement of the cyto- and biochemical methods the presence of more and more chemical substances could be demonstrated in the NST. A summary of these can be seen in the Table 3. Their number is likely to increase in the near future. (Noteworthy, that substances listed in Table 3 were described in the NST in general without referring to any subdivision. Consequently, their presence in the NST does not eo ipso indicates their role in the cardiovascular regulation.)

    Biogenic amines were demonstrated in the NST by histochemical, immunocytochemical and biochemical methods. The NST stands out with its highest adrenaline and PNMT concentrations in the CNS (12,23, 32). Conversely, the serotonin (27) and the choline acetyltransfese (21) contents the nucleus are relatively low. Vasopressin and its carrier protein, neurophysin were demonstrated in nerve terminals, too (38,39,40). They are supposed to be of hypothalamic origin. Nerve terminals containing substance P (6,9,13), neurotensin (44,45), and enkephalin (10,13,17,37,43) are thought to have intranuclear origin. Recently, terminals containing α-MSH were found in the NST (16), but their origin is still unknown. The high prostaglandin concentration of the nucleus (5) seems to be worth

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