Central Nervous System Circuitry and Peripheral Neural Sympathetic Activity Responsible for Essential Hypertension

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Central Nervous System Circuitry and Peripheral Neural Sympathetic Activity Responsible for Essential Hypertension Fuad Lechin* and Bertha van der Dijs Department of Physiological Sciences, Sections of Neurochemistry, Neurophysiology, Neuroimmunology and Neuropharmacology; Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas, Venezuela Abstract: Both clinical and experimental studies dealing with patients affected by idiopathic or essential hypertension (EH) are devoted to the great deal of physiological, pharmacological and pathological as well as therapeutical issues of EH. However, most articles devoted to EH do not refer to the central nervous system mechanisms underlying this disease and the channels which allow that these mechanisms are funneled to the peripheral autonomic nervous system and trigger this cardiovascular disorder. In the present review article we attempted to reach this target devoted to the central nervous system circuitry involved in the cardiovascular pathophysiology. We postulated that EH depends on the predominance of the binomial A5 noradrenergic (NA) nucleus + median raphe serotonergic (5-HT) nucleus over the (A6)-NA + dorsal raphe-5HT nuclei. This hypothesis receives additional support from our results obtained throughout the neuropharmacological therapy of this type of neurophysiological disorder. Our therapeutical strategy is addressed to enhance the activity of the (A6)-NA + dorsal raphe-5HT binomial circuitry.

Key Words: Blood pressure, adrenal system, noradrenaline, adrenaline, serotonin, acetylcholine, central neurotransmitters, monoaminergic system, locus coeruleus. INTRODUCTION A great bulk of information dealing with this issue has been published in both clinical and scientific journals. However, neuroscientists do not treat patients and clinicians have not enough knowledge dealing with the central nervous system (CNS) circuitry, which is necessary for the assimilation of that information which would allow the outline of adequate therapeutical strategies. These reflections leaded us to attempt the collection of the most significant research studies referred to this target and to join them in order to facilitate the understanding of such interdisciplinary information. With this purpose, we will refer to the EH disease and to the specific mechanisms plus the CNS circuitry underlying it. In addition, we will present the links that integrate the chain over which this physiological disorder travels from inside CNS to the peripheral autonomic nervous system (ANS), after crossing the blood brain barrier (BBB). That CNS plus peripheral crosstalk is driven throughout three main channels: neural sympathetic, adrenal sympathetic and parasympathetic activities. We will present also anatomical, physiological, pathophysiological, and pharmacological evidence, which support our point of view. Furthermore, we will summarize the CNS circuitry involving noradrenergic (NA), adrenergic (Ad), serotonergic (5HT), and acetylcholinergic (ACh) systems that play some role into the mechanisms responsible for EH. In addition, we will also refer to those peptides and hormones which act as mediators and cooperate or antagonize with those neurotransmitters, i.e. angiotensin, renin, neuro*Address correspondence to this author at the Apartado 80.983, Caracas 1080-A, Venezuela; E.mail: [email protected] Received: August 5, 06, Revised: August 28, 06, Accepted: August 30, 06

1567-2026/06 $50.00+.00

tensin, corticosterone, adrenocorticotropin hormone (ACTH), corticotropin releasing hormone (CRH), etc. Finally, we will point out that the peripheral sympathetic system depends on two well differentiated CNS plus peripheral circuitries: a) neural sympathetic and b) adrenal sympathetic. These two branches may act in association or dissociation; the lack of information dealing with this issue has became muddy the clear understanding of many cardiovascular and other diseases which frequently leads to fatal therapeutical errors (Lechin et al., 2002a). This example obliges clinicians to be aware that most drugs they administer to their patients act at both sides of the BBB. ACETYLCHOLINERGIC PLUS MONOAMINERGIC CIRCUITRY ACh-Neuronal System Although these neurons are mostly interneurons (short axons neurons) which crowd the midbrain structures, including all regions of the midbrain (medulla, pons and suprapontine) some ACh neurons are clustered into well defined nuclei, which send axons to long distance nuclei. They integrate the pontine reticular formation, which includes the pedunculo-pontine nucleus (PPN) which receives axons from all monoaminergic nuclei. In turn, some PPN-ACh grouped neurons send also axons to those monoaminergic nuclei that are included amongst these areas. Thus, PPN-ACh neurons are interconnected with all NA, DA, 5HT and Ad nuclei (Lechin et al., 1979a, 1989a, 2002b). At the medullary zone, ACh neurons are also organized within several nuclei which interchange axons with all types of monoaminergic neurons. These ACh neurons are grouped as sensitive and motor nuclei which integrate a network responsible for the peripheral parasympathetic system (Agren et al., 1986; Anderson et al., ©2006 Bentham Science Publishers Ltd.

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2000; Bhaskaran and Freed, 1988; Borsody and Weiss, 2005; Egan and North, 1985; Freed et al., 1985; Grandison and Meites, 1976; Heym et al., 1981; Jacobs and Cohen, 1976; Kawahara et al., 1999; Lechin et al., 1979a, 2006a; McQuade and Sharp, 1995, 1997; Morilak et al., 1986; Park 2002; Pudovkina et al., 2001, 2002; Pyneiro and Blier, 1996; Saavedra et al., 1976; Singewald et al., 1993, 1995; Young et al., 1978). The area postrema (AP), the nucleus tractus commisuralis, the nucleus tractus solitary (NTS), the nucleus dorsalis vagi, the nucleus nervi hypoglossi, the nucleus ambiguus, the nucleus reticularis lateralis and some other minor nuclei, integrate a complex sensory-motor network which contributes to the modulation of the peripheral vs CNS interaction (Lechin et al., 1979a, 1989b; 2002c). Medullary but not midbrain ACh neurons interchange long distance axons with pontine and spinal structures. Furthermore, the AP is located outside the BBB and receives direct information from circulating neurotransmitters, which allows adequate and quick responses to stimuli arising from outside the BBB (Lechin et al., 1979a, 1989b, 2002c, 2005). This compliance medullary ACh network contributes to the physiological peripheral stability. For instance any blood pressure (BP) fall is transmitted by the medullary parasympathetic sensorial structures to both the medullary adrenergic and the pontine noradrenergic nuclei which produce adequate adrenal glands + neural sympathetic responses, addressed to restore the homeostasis (Lechin et al., 1989e). Other ACh neurons are located at the intermediolateral spinal levels. These neurons are presynaptic neurons whose axons reach the adrenal glands (cervical + thoracic segments) and the sympathetic ganglia (lumbar segment). The former ACh neurons receive modulatory axons from medullary and hypothalamic structures but not from pontine or suprapontine nuclei. Conversely, lumbar sympathetic neurons receive axons from the pontine (A5)-NA neurons which are the most important nucleus whose firing activity is positively correlated with the peripheral neural sympathetic drive (Lechin et al., 1989e). According to all the above, we might summarize it saying that both medullary and spinal ACh neurons are the last links of the two branches of the circuits responsible for the adrenal and neural sympathetic activity. These circuitries have enough flexibility to avoid extreme oscillations of the BP in normal but not in subjects affected by EH and/or in stressed subjects. Monoaminergic Circuitry It is integrated by noradrenaline, adrenaline, dopamine (DA) and serotonin, glutamate and GABA neurons which are located at the pontine, suprapontine, medullary, and spinal regions. Noradrenergic Circuitry It includes two main pontine nucleus plus other medullary neurons. The A6 + A7 + A4 noradrenergic neurons integrate the locus coeruleus (LC). This latter structure is the more crowded NA nucleus. LC-NA or (A6)-NA sends axons to almost all CNS areas (Lechin et al., 1979a, 1989b, 2002c). Although (A6)-NA neurons are excited by any BP fall which triggers NA release from LC-axons at several CNS structures addressed to re-establish the acute hypotension episode, this

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nucleus is negatively correlated with EH. For instance, excitation of this nucleus with glutamate and with neurotensin triggers BP fall (Borsody and Weiss, 2005; Dampney 1994b; Murase et al., 1993, 1994). Furthermore, spontaneously hypertensive rats (SHR), the mammal model of EH, have lower than normal number of LC-NA neurons when compared with non-hypertensive rats (Kaehler et al., 2004; Yao and Lawrence, 2005). In addition, SHR present with an increased metabolic rate at the LC-NA neurons which favors the exhaustion of them thus, a negative rather than positive physiological correlation between EH and (A6)-NA, should be assumed (Folkow 1975; Yao and Lawrence, 2005). Noradrenergic CNS circuitry also includes the (A5)-NA nucleus. Neurons of this nucleus are located at the subcoeruleus area and extend until the medullary zone (Byrum and Guyenet, 1987; Korner et al., 1987). (A5)-NA axons reach subcortical areas, mainly, which include pontine, mesolimbic, hypothalamic, medullary and spinal zones. Several anatomical connections differentiate both the (A5) from the (A6) NA nucleus. For instance, although the medullary C1Ad nuclei send axons to both the (A6)- and (A5)-NA nuclei, the latter but not the former innervates the C1-Ad nuclei, directly. The (A5)-NA nucleus sends and receives axons from almost all CNS nuclei involved in cardiovascular physiology (Dormer 1984; Korner et al., 1987; Tanaka et al., 1996). These include medullary and hypothalamic structures and the nucleus centralis of the amygdala (CEA), which is also heavily innervated by the (A6)-NA axons. Special mention should be made to the (A5)-NA and (A6)-NA spinal axons, whereas the former innervate the sympathetic (preganglionic) neurons (Dabsys et al., 1988), the latter sends axons to the anterior (motor) and posterior (sensitive) spinal areas (Drye et al., 1989). However, both the A6 and the A5 noradrenergic neurons send axons to the hypothalamus and share the innervation of several nuclei at this area (Fritschy and Grzanna, 1990; Krukoff et al., 1997; Liu et al., 1991; Owens et al., 1991a, 1991b; Schlenker 2005). Both (A6)-NA and (A5)-NA nuclei interchange inhibitory axons. Noradrenaline released from them triggers inhibition of the innervated NA neurons which are crowded with alpha-2 presynaptic receptors. Both (A6)- and (A5) NA nuclei send and receive axons to and from the ACh neurons dispersed and or grouped into nuclei which are responsible for the relay of peripheral parasympathetic information. These interchange of axons allows the acute buffering of BP changes, which are involved in the pathophysiological mechanisms underlying non-essential hypertensive syndromes (Lechin et al., 1979b, 1989e, 2005). Noradrenergic medullary nuclei include the A1-NA and the A2-NA nuclei. These nuclei are integrated into a network of adrenergic, acetylcholinergic and serotonergic nuclei whose main role consists in the modulation of peripheral vs CNS crosstalk. This network acts as a compliance system that produces quick compensatory responses and avoids excessive cardiovascular oscillations. However, these NA medullary nuclei do not play a significant role into the mechanisms underlying EH (Dampney 1994a; Lai et al., 1989; Schneider et al., 1995; Sun 1995; van Giersbergen et al., 1992; Willette et al., 1984; Yusof and Coote, 1988).

CNS Circuitry & Essential Hypertension

Adrenergic Circuitry Adrenergic circuitry arises from the medullary C1-Ad and C2-Ad nuclei. The C1-Ad nuclei are located at the rostral ventrolateral area and constitute the crossroad to where converge a great deal of NA, 5-HT, ACh, glutamate, GABA, and other types of axons. In addition, it acts like a frontier point heavily connected with outside plus inside arriving ways and receiving many different types of travelers. These nuclei send axons to both pontine and medullary NA-nuclei which give back direct (A5-NA) inhibitory and indirect (A6NA) inhibitory or excitatory drives. Similar interconnections between the C1-Ad nuclei with serotonergic and acetylcholinergic nuclei have been demonstrated. Serotonergic inputs are able to inhibit C1-Ad neurons by acting at 5HT-1A receptors located at these nuclei (Johnson et al., 2004). In addition, the medullary serotonergic nuclei raphe magnus (RM), raphe obscurus (RO) and raphe pallidus (RP) also send direct and indirect drives to the parasympathetic nuclei which integrate the dorsal vagal complex and to the C1-Ad nuclei (Briggs 1977; Consolo et al., 1994; Hilgert et al., 2000; Katsu 2001). Evenmore, the pontine 5HT periaqueductal gray (PAG) sends monosynaptic inhibitory axons to the C1-Ad medullary nuclei (Farkas et al., 1998). We have cited previously that direct inhibitory axons arrive to the C1-Ad nuclei from the (A1)-NA and (A2)-NA medullary nuclei. This NA vs Ad dialogue along with the dialogue with ACh medullary nuclei, responsible for the peripheral parasympathetic activity represent the first floor of the CNS building which exerts a monitorial role and allows to increase or decrease the BP and heart rate, according with the physiological circumstances. However, this medullary adrenergic circuitry is not responsible for the raised BP registered in EH. Evenmore, taking into account that the C1-Ad nuclei send excitatory axons to the spinal sympathetic preganglionic neurons (cervical and thoracic, but not lumbar segments), whose ACh preganglionic sympathetic axons innervate the adrenal glands, the C1-Ad medullary system is directly responsible for the adrenal glands secretion (70-80% of Ad + 10-20% of NA + DA) (Lechin et al., 2002c). At the peripheral level, Ad plasma levels reach minimal values 10 min after the supine resting condition. This decrease reaches zero values during REM sleep stage. Conversely, NA plasma levels show slow rather than abrupt reduction throughout the sleep cycle and do not reach zero values during REM sleep (Lechin et al., 2004c). These findings are consistent with the fact that (A6)-NA but not (A5)NA neurons (responsible for neural sympathetic activity) reach zero firing activity during REM sleep. Taking into account that both (A6)-NA and DR-5HT neurons are absolutely silent during REM sleep stage, it allows to understand the mechanisms that favor the appearance of EH in patients affected by sleep apnea and other sleep disorders. The short REM sleep latency registered in both depressed and obstructive sleep apnea patients would favor the premature and prolonged predominance of the (A5)-NA over (A6)-NA, in essential hypertensive patients during nocturnal periods (Lechin et al., 2004b). Exhaustion of both the LC-NA and the DR-5HT derived from a recovery’s deficit during nocturnal sleep periods will favor the predominance of the (A5)NA and the MR-5HT neurons. Studies carried out in our

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laboratory and from other authors have demonstrated that essential hypertensive patients do not reach REM sleep stage, at which period both (A6)-NA and DR-5HT neurons should be recovered from the diurnal stress (Lechin et al., 1995, 2002b). We will discuss this issue further. Noradrenergic Circuitries and Essential Hypertension Noradrenergic Locus Coeruleus Nucleus and Essential Hypertension The locus coeruleus LC or (A6)-NA pontine nucleus constitutes the biggest noradrenergic CNS nucleus. It is located at the dorsal pontine medial zone. It also includes NA neurons located at the lateral wings (A7)-NA neurons. Axons arising from the LC innervate the cortex, hippocampus, limbic and mesolimbic structures, hypothalamus, medulla and anterior + posterior spinal zones. In turn, the LC receives direct and/or indirect monosynaptic and polysynaptic drives from the above areas (Benarroch et al., 1983; Lechin et al., 1989e, 1993) (Fig. 1). Physiological data demonstrated that any acute BP fall triggers fast excitation of LC-NA neurons and BP recovery; thus, this nucleus plays a pivotal role in the maintenance of cardiovascular homeostasis (Elam et al., 1986). This physiological role played by the LC-NA nucleus may be explained by its afferents plus efferents connections with other CNS structures involved in the BP regulatory mechanisms. For instance, the LC-NA nucleus receives axons from the parasympathetic (ACh) medullary nuclei and the adrenomedullary C1 nuclei (Ennis and Aston-Jones, 1986; Astier et al., 1990). In addition, the (A6)-NA sends direct axons to the former (ACh) nuclei (Baraban and Aghajanian, 1981; Gorea and Adrien, 1988; Mundey et al., 1994; Szabo and Blier, 2001) and polysynaptic drive to the latter (Lambas-Senas et al., 1986; Petrov et al., 1993; Pieribone et al., 1988; Sawchenko et al., 1985; Tanaka et al., 1986). According to these links, the (A6)-NA nucleus may provoke acute and fast bridling of the parasympathetic neurons and also indirect modulation of the adrenal sympathetic system. According to the above, although the LC-NA neurons are able to modulate BP oscillations they are not responsible for the sustained diastolic blood pressure (DBP) increase occurring in EH (Lechin et al., 1993, 2004a; Ogawa 1978; Sved and Felsten, 1987; Svensson 1987). The (A6)-NA nucleus is the first link of the stress chain. Noradrenaline released from LC-NA axons at the paraventricular hypothalamic nucleus (PVN), excites the secretion of CRH. This hormone is released at the hypothalamic (median eminence) area which projects to the hypophysis provoking the secretion of ACTH (Burchfield 1979; Conti et al., 1997; Groves et al., 2005; Kobayashi et al., 1975; Kvetnansky et al., 1975; Lechin et al., 1996a; Swenson and Vogel, 1983; Van Gaalen et al., 1997; Whitnall 1983). This latter excites the release of corticosterone from the adrenal cortical glands. The other branch of LC-NA excitatory drive reaches the posterior hypothalamic area which sends excitatory axons to the C1-Ad medullary nuclei (Dampney et al., 1987; Gauthier 1981; Robertson et al., 1979; Schreiberg and Dunaieva, 1976; Whitnall 1993). Summarizing, the LC-NA nucleus sends polysynaptic excitatory drives to both adreno-cortical and adreno-medullary areas which release cortisol and Ad to

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Fig. (1). Central nervous system (CNS) circuitry involved in blood pressure (BP) regulation. The (A5)-NA pontomedullary and the C1Ad medullary nuclei are responsible for neural and adrenal peripheral sympathetic activities, respectively. Neural sympathetic activity is responsible for NA release from sympathetic nerves, whereas adrenal sympathetic activity depends on the catecholamines released from the adrenal glands (80-90% of adrenaline (Ad) + 10-90% of noradrenaline (NA) + dopamine (DA). Both A5 and A6 noradrenergic neurons interchange inhibitory axons which release NA at alpha-2 somatodendritic synaptic autoreceptors, located in the innervated NA neurons, thus, they are able to modulate each other, during physiological situations. However, predominance of one of them may occur during some pathophysiological circumstances. Excitatory and/or inhibitory drives targeting those NA nuclei are responsible for the proportional contribution of those NA nuclei to the peripheral sympathetic activity. The (A6)-NA neurons or locus coeruleus LC receive excitatory axons [glutamate, and acetylcholinergic (ACh)] from cortical and pontine + medullary areas, respectively. In addition, GABAergic and serotonergic axons are responsible for the inhibition of (A6)-NA neurons. Serotonergic inhibitory axons arrive from the DR and MR-5HT axons. Acetylcholinergic axons arise from the pendunculopontine nucleus (PPN) and the medullary parasympathetic structures. This (A6)-NA vs pontomedullary (ACh) interaction explains how any blood pressure fall triggers a (A6)-NA excitatory response able to restore the acute hypotensive phenomenon. The C1-Ad medullary nuclei send inhibitory axons to the (A6)-NA neurons. Adrenaline released from these axons inhibits the NA neurons of the A6 LC neurons. According to it, both ACh and Ad medullary neurons excite and inhibit (A6)-NA neurons. Conversely, (A6)NA neurons inhibit ACh medullary neurons directly, and modulate C1-Ad activity throughout polysynaptic drives. Excitation of the (A6)-NA neurons provokes adrenal gland secretion + (A5)-NA inhibition. These findings are consistent with the (A6)-NA positive correlation with adrenal sympathetic and negative correlation with neural sympathetic activity. Conversely, excitation of the (A5)-NA neurons increases neural sympathetic activity and inhibits both the C1-Ad and (A6)-NA neurons. MR-5HT neurons cooperate with (A5)-NA neurons at the circuitry integrated by the CEA, anterior hypothalamus and bed nucleus of stria terminalis (BNST). This circuitry is positively correlated with neural sympathetic activity.

CNS Circuitry & Essential Hypertension

the blood, respectively. However, the LC-NA nucleus does not excite neural sympathetic activity, responsible for EH (Astier et al., 1986; Borsody 2005; Ennis and Aston-Jones, 1987; Gurtu et al., 1984; Lawler et al., 1985; Lechin et al., 1993, 2004a). A bulk of information allows associate EH with a deficit rather than an excess of LC-NA activity (Conti et al., 1997; Engberg et al., 1987; Miyawaki et al., 1992; Van Gaalen et al., 1997). With respect to this, it is a well-known fact that the rat model of EH (SHR) are characterized by a lower than normal number of NA neurons at the LC nucleus. Others have demonstrated that this finding should be also associated with the increased metabolic rate displayed by the NAneurons at the LC-NA nucleus registered in SHR (Engberg et al., 1987; Folkow 1975). Additional information supports this hypothesis (Koulu et al., 1986b; McDougall et al., 2005; Russell et al., 1995). Furthermore, experimental centrally induced hypertension is produced by chemical degeneration of locus coeruleus in the rat (Ogawa et al., 1979). Even more, SHR are the rat model of hyperactive + hyper kinetic (rats and children). With respect to this, it is a welldemonstrated fact that this syndrome is due to a deficit of NA and DA at cortical level, which receives NA axons from the LC but not from other NA nuclei. The low cortical levels of DA would be explained because the VTA (A10) dopaminergic neurons, which innervate the brain cortex, depend on the excitatory drive arising from the LC-NA nucleus (Russell et al., 1995). These VTA-(DA) neurons are crowded by alpha-1 adrenoceptors which are excited by the NA released from the (A6)-NA axons (Lechin et al., 2002b). The LC-NA neurons innervate four other CNS areas that are closely involved into the circuitry responsible for BP regulation which include the DR (Gorea and Adrien, 1988) and the MR serotonergic nuclei (Adell and Artigas, 1999; Saavedra et al., 1976), the anterior hypothalamus (Ogawa et al., 1979), and the CEA (Oishi et al., 1979; Watanabe et al., 2003). The synergism with the DR and the antagonism with the MR at these other three areas are consistent with the postulation that the LC-NA activity is negatively correlated with the essential hypertensive syndrome (Fenik et al., 2002; Lechin et al., 2006a). Evenmore, the fact that LC-NA nucleus interchanges inhibitory axons with the (A5)-NA neurons, which are responsible for the neural sympathetic activity, closes the circle which reinforces our postulation (Kostowski 1979; Lechin et al., 1989b; Levitt and Moore, 1974; Lindvall and Bjorklund, 1974; Marwaha and Aghajanian, 1982; O’Donohue et al., 1979). Furtherly, we will offer additional support to this issue. Noradrenergic A5 (Sub-Coeruleus) Nucleus and Essential Hypertension These neurons are located at the pontine + medullary regions. They interchange axons with the (A6)-NA or locus coeruleus neurons and in addition, innervate many CNS structures which also receive LC-NA axons. However, both (A6)-NA and (A5)-NA axons innervate complementary CNS areas mostly. For instance, few (A5)-NA axons reach cortical levels which are maximally innervated by LC-NA axons. Conversely, (A5)-NA and not LC-NA axons innervate several medullary nuclei, directly (Korner et al., 1987; Li et al., 1992). Special mention should be made with respect to the

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C1-Ad medullary nuclei which are directly inhibited by (A5)-NA axons (Byrum and Guyenet, 1987; Fenik et al., 2002; Loewy et al., 1994). This adrenergic + noradrenergic circuitry underlies the physiological mechanisms separating both neural and adrenal sympathetic activities, because whereas C1-Ad axons innervated both (A5)-NA and (A6)NA nuclei, the former but not the latter sends monosynaptic axons to the C1-Ad nuclei (Fenik et al., 2002). This Ad + NA circuitry explains why neural and adrenal sympathetic activity can act associated or dissociated (Lechin et al., 2005; Young et al., 1984). The above anatomical plus physiological crosstalk explains why excessive C1-Ad activity is able to inhibit both (A5)-NA + (A6)-NA neurons. Conversely, excessive LC-NA drive inhibits (A5)-NA and excites C1-Ad. This latter excitation is exerted throughout polysynaptic mechanisms that include the posterior hypothalamic nuclei. Finally, hyperactivity of the (A5)-NA nucleus enhances neural sympathetic activity (by acting at the spinal sympathetic preganglionic neurons) and in addition, inhibits adrenal sympathetic activity through the release of NA at the C1-Ad medullary nuclei (Clark et al., 1991; Fritschy and Grzanna, 1990; Gurtu et al., 1984; Lechin et al., 2006b; Malpas 1998; Ward and Gunn, 1976). This C1-Ad + (A5)-NA + (A6)-NA crosstalk would be interfered in the EH disorder because the deficit of LCNA activity, responsible for the compliance mechanisms necessary to avoid the absolute predominance of the neural sympathetic activity (A5-NA) over the adrenal sympathetic activity C1-Ad. The above postulation is supported preferentially by findings indicating that small dose of sibutramine, which at low doses, selectively excites (A5)-NA neurons, mainly, triggers an abrupt decrease of Ad plasma levels plus an increase of DBP + NA and DA plasma levels rises. In other worlds, the drug excited neural sympathetic activity selectively but inhibited adrenal sympathetic activity. Our findings explain why this drug is contraindicated in EH patients (Lechin et al., 2006b). Summarizing all the above, whereas the (A5)-NA activity excites neural sympathetic activity and inhibits adrenal sympathetic activity, the (A6)NA activity inhibits neural sympathetic drive and may excite adrenal sympathetic activity. Furthermore, both the (A5)-NA and (A6)-NA axons inhibit CNS-parasympathetic nuclei (Drye et al., 1989; Groves et al., 2005). Noradrenergic (A5)-NA neurons are also involved in other polysynaptic mechanisms underlying BP regulation which would play a role in the pathophysiology of EH. For instance, (A5)-NA axons reach both the CEA and the anterior hypothalamic area, which are maximally involved in the CNS circuitry underlying EH (Dun et al., 1995). In addition, (A5)-NA neurons interchange axons with both the DR and MR serotonergic nuclei, whose roles in EH have been heavily investigated (Lechin et al., 1979b, 1989e). Other research studies shed additional light on the intimate mechanisms underlying the (A5)-NA and (A6)-NA interaction. For instance, Drye et al. (1989) demonstrated that there exist two type of neurons at the (A5)-NA nucleus a) pressor and b) depressor neurons. The former sends axons to the spinal sympathetic neurons whereas the latter innervate the NTS-ACh neurons. Pressor neurons release the excitatory glutamate neurotransmitters, whereas depressor neu-

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rons release NA. With respect to this, Loewy et al. (1986) demonstrated that destruction of these latter neurons reduces the depressor response significantly. Conversely, destruction of the (A5)-spinal link triggers the opposite effect. Finally, findings by Verdecchia et al. (1993) demonstrated that essential hypertensive women had a blunted nocturnal fall in BP, whereas Williams and Reiner (1993) demonstrated that these patients do not present REM sleep stage during their nocturnal sleep cycle. With respect to this, Lechin et al. (2004c) demonstrated that NA plasma levels reach minimal values at this period in normal but not EH patients at which level DBP is detected in the latter but not in the former subjects. Thus, essential hypertensive patients show neither the DBP fall nor the NA plasma level disappearance throughout their electroencephalographic sleep investigation plus circulating neurotransmitters assessment, respectively (Lechin et al., 2004b). The above findings give additional support to the postulation that the (A5)-NA pontine neurons of essential hypertensive patients do not show the absolute normal fading, which occurs in normal subjects at the REM sleep period. This phenomenon fits well with the lower than normal (A6)-NA over (A5)-NA bridling, depending on the reduced number of (A6)-NA neurons presented by both SHR and essential hypertensive humans. The sleep disorder presented by essential hypertensive patients merits some additional comments. For instance, DR-5HT neurons fade at the delta sleep period whereas the MR-5HT neurons show a less fast and total fall throughout this sleep period (Lechin et al., 2002b; Lechin and van der Dijs, 2005). The fact that DR5HT neurons but not the MR-5HT neurons are closely positively correlated with the (A6)-NA neurons suggests that the absence of DBP fall registered in essential hypertensive patients might be linked to predominance of the MR-5HT neurons. With respect to this, it should be remembered that the DR-5HT but not the MR-5HT neurons activity parallels (A6)-NA neuronal activity. Even more, a MR-5HT vs (A6)NA antagonism has been exhaustively demonstrated (Lechin et al., 2006a; Saavedra et al., 1976). The absence of those three physiological parameters in essential hypertensive patients: REM sleep appearance, NA plasma level disappearance and DBP fall might be dependent of both (A5)-NA + MR-5HT hyperactivity. A detailed analysis of both anatomical and physiological mechanisms involving CNS-NA neurons is necessary in order to understanding their role in the pathophysiology of EH. For instance, it is known that the CNS-NA system is integrated by two distinct groups of cells in the brainstem: 1) The nucleus LC (corresponding to the A4-NA + A6-NA + A7-NA cell groups) is the source of the majority of NA projections throughout the neuroaxis which innervate areas such as the frontal cortex, hippocampus, amygdala, cerebellum, hypothalamus and spinal cord. These projections are included in the dorsal NA bundle. 2) Efferents from the lateral tegmentum (corresponding to the A1, A2, and A5 cell groups) form the ventral NA bundle, which have less extensive projections. These latter provide prominent innervation to the hypothalamus and also innervate the areas of the septum and the extended amygdala nuclei including the bed nucleus of the stria terminalis (BNST). Those two groups of NA neurons display opposing effects (Kostowski, 1979). According to the above, any deficit of the LC-NA activity

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would be reflected in the predominance of the other group. This physiological information fits well with our postulation that the deficiency of the LC-NA (A6) neurons demonstrated in SHR should favor the A5-NA predominance (Clark et al., 1991; Fritschy and Grzanna, 1990; Gurtu et al., 1984; Korner et al., 1987; Sinha et al., 1984). Much physiological evidence demonstrated that both types of NA neurons play distinct role in the mechanisms responsible for BP regulation. With respect to this, it has been demonstrated that (A6)-NA neurons cooperate with the C1-Ad neurons to trigger systolic BP increase, mainly, whereas the (A5)-NA neurons are mainly involved in the maintenance and enhancement of DBP (Fenik et al., 2002). Even more, it has been demonstrated that these neurons send direct inhibitory axons to the C1-Ad medullary and the (A6)NA nuclei (Lechin et al., 2006b; Suzuki et al., 1981). The above findings put over the table the role played by the (A5)NA and the (A6)-NA neurons in the regulation of BP responsible for EH. With respect to this, Singewald et al. (1993) demonstrated that the release of NA in the LC is triggered by signals originated from peripheral baroreceptors. Noradrenergic neurons of this pontine nucleus respond to haemodynamic signals originating from peripheral baroreceptors, contributing to the CNS homeostasis of BP. With respect to this, adrenergic input originated from the C1-Ad neurons inhibits the activity of the (A6)-NA neurons. However, despite that the LC-NA receives direct axons from the C1-Ad nucleus, the (A6)-NA nucleus modulates the C1-Ad throughout polysynaptic (midbrain and hypothalamic) mechanisms. These findings fit well with the postulation that the (A4)-NA + (A6)-NA pontine neurons are responsible for the labile and short lasting BP rises, whereas other NA neurons (A5) are responsible for the persistent DBP rise registered in EH. This postulation receives additional support from other findings which demonstrated that the close anatomical plus physiological correlation found between the (A6)-NA and DR-5HT nuclei, is not registered between the (A6)-NA and the MR-5HT neurons. With respect to this, we will afford a bulk of evidence which supports the primary role exerted by these latter serotonergic neurons in the pathophysiology of EH. All the above is consistent with findings showing that essential hypertensive patients present with increased NA but not Ad plasma level (Christensen 1983; Kjeldsen et al., 1989; Lechin et al., 1993). This NA predominance is augmented during the orthostasis and moderate exercise challenges (Goldstein et al., 1983; Lake et al., 1977; Lechin et al., 1996c, 1996d; Neil and Loewy, 1982; Ogawa 1978; Robertson et al., 1979). Other findings discard the possible role played by the C1Ad neurons in the pathophysiology of EH. For instance, bilateral destruction of these nuclei triggers profound fall in BP, however normalization is registered after 4-5 days of this experimental procedure (Dampney et al., 2003). Therefore, the physiological role played by this adrenal sympathetic medullary system should be referred to clonic but not tonic sustained excitatory drive. Furthermore, it has been shown that neural sympathetic hyperactivity is responsible for the raised DBP registered in EH patients. With respect to it, this parameter depends on the lumbar sympathetic spinal neurons which send ACh-axons to sympathetic ganglia. These ganglia send NA postsynaptic axons to muscle and

CNS Circuitry & Essential Hypertension

vascular areas at which levels release NA and DA. With regard to this, it should be known that there exists a DA-pool at these terminals which release dopamine before noradrenaline. The former modulates the latter by acting at presynaptic DA-2 receptors located at these terminals. Excessive release of DA is responsible for the well known orthostatic hypotension (Mannelli et al., 1988). Other findings demonstrated that hyperactivity of neural sympathetic system inhibits adrenal glands release of Ad. This phenomenon occurs in EH (Fenik et al., 2002). Sympathetic preganglionic ACh spinal neurons receive excitatory and inhibitory axons. Noradrenergic (A5) axons release glutamate at this level as its main excitatory neurotransmitter (Neil and Loewy, 1982). However, other neurotransmitters are also released at this spinal level including GABA, glycine, angiotensin II, enkephalins, substance P, neuropeptide Y and others (Dampney et al., 2003). Serotonin, which arises from the axons of the medullary RP, is also released at sympathetic preganglionic neurons. This neurotransmitter would play a modulatory rather than excitatory effect (Senba et al., 1993). Axons arising from the C1Ad and the paraventricular hypothalamic nuclei innervated the cervical and some thoracic segments but do not reach lumbar sympathetic neurons (Strack et al., 1989). Excitation of the C1-Ad nuclei elicits cardiovascular and noncardiovascular effects associated with adrenal glands secretion (Dampney et al., 2003). These findings are consistent with others showing that axons from these nuclei innervate the intermediolateral spinal horns in only a very restricted part of the thoracic cord, while others project directly to widely separated thoracic segments (Cox and Brody, 1989; McAuley et al., 1989; Minson et al, 1994). Therefore, the physiological role played by this adrenal sympathetic medullary system should be referred to clonic but not sustained excitatory activity. This postulation fits well with findings showing that the C1-Ad medullary neuronal circuitry is highly crowded with angiotensin receptors. Activation of these receptors leads to a rise in BP and sympathetic vasomotor activity (Dampney et al., 2003). Endogenous angiotensin is tonically released from nerve terminals in the C1Ad nuclei and triggers adrenal glands secretion. Glutamatergic axons are also highly involved in this effect (Fenik et al., 2002). Other findings by Fenik et al. (2002) demonstrated that excitation of the (A5)-NA nucleus with glutamate increases DBP. Several mechanisms converge to provoke these findings. The (A5)-NA axons inhibit both the C1-Ad medullary nuclei and the cholinergic NTS. In addition, (A5)-NA axons innervate the CEA (Sanchez et al., 2003), which is maximally involved in the circuitry responsible for EH, since the destruction of this nucleus annuls the EH in SHR. Other findings demonstrate that (A5)-NA axons reach the LC-NA neurons which are inhibited by NA released at this level by acting at alpha-2 presynaptic receptors located at this nucleus (Fenik et al., 2002; Lechin et al., 1979b, 1989a). Other noradrenergic nuclei like A1 and A2 medullary nuclei interchange axons with C1-Ad and C2-Ad nuclei, serotonergic raphe magnus, raphe obscurus and raphe pallidus medullary nuclei which interact with the medullary parasympathetic structures, including the NTS, dorsal motor

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nucleus of the vagus and the AP all of which display modulatory activity between the peripheral (outside the BBB) and CNS circuitry involved in the maintenance of the BP homeostasis (Lechin et al., 1989a, 1989c). However, this medullary circuitry does not play a pivotal pathophysiological role into the mechanisms responsible for EH. With respect to this, the AP nucleus plays a special role. This medullary structure is located outside the BBB and is crowded by serotonergic receptors (5HT-3) which are excited by circulating serotonin. Thus, any increase of plasma 5HT provokes parasympathetic activation and enhances the acetylcholine release at the enterochromaffin cells which release more serotonin to the blood. This positive feedback mechanism is known as the Bezold Jarisch reflex, responsible for abrupt BP fall. However, the AP also interchanges axons with the adrenal sympathetic medullary structures responsible for counteract any hyperparasympathetic activity, i.e. the C1-Ad rostral ventrolateral medullary nuclei. Finally, this complex medullary network interchange excitatory plus inhibitory drives with both pontine and hypothalamic structures which receives information and exports corrective decisions. In spite of the above, this malleable network does not play a primordial role into the pathophysiology of EH (Lechin et al., 2005). Serotonergic Circuitry and Essential Hypertension Six serotonergic nuclei are located at the midline of the pontine and medullary regions: the median raphe (MR) or nucleus centralis superioris = B8 + B9 serotonergic nuclei; the dorsal raphe (DR) = B7, the periaqueductal gray (PAG) or B6, the raphe magnus (RM) or B5; the raphe obscurus (RO) = B4 and the raphe pallidus (RP) or B3 nuclei. This latter sends excitatory axons to the spinal sympathetic neurons and contribute to the adrenal glands secretion. In addition, RP axons innervate also the spinal thoracic + lumbar segments responsible for neural sympathetic activity (Lechin et al., 2002c). Medullary serotonergic nuclei receive inhibitory axons from the pontine DR-5HT nucleus. Disinhibition of the RP5HT from this bridle is responsible for the nocturnal jerking, during REM sleep, at which period the DR but not the RP displays zero firing activity. This phenomenon is consistent with the fact that RP-serotonergic axons innervate also the motor (anterior) spinal areas. This phenomenon is magnified during the "called" serotonergic syndrome. The above findings help to understand that the role played by medullary serotonergic nuclei is not a primary but secondary role (Lechin et al., 2002b). This inhibition of the RP-5HT neurons exerted by the DR-5HT axons supports the postulation that this factor plays a primary role into the pathophysiologic mechanisms underlying EH (Fig. 2). Summarizing all the above, although all serotonergic nuclei are involved into the physiological mechanisms responsible for BP regulation, the pontine rather than the medullary nuclei may play a primordial role into the pathophysiology of EH. A great bulk of experimental, clinical and therapeutical data supports this postulation. With respect to this, we will present evidence supporting our point of view. This postulation is reinforced by the demonstration that a MR over DR predominance underlies this syndrome (Lechin et al., 2006a).

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Fig. (2). Central nervous system (CNS) circuitry involved in neural sympathetic activity (NSA). Disappearance of NSA is registered after the destruction of lumbar sympathetic pre-ganglionic cholinergic (ACh) neurons, and/or the pontine-medullary (A5)-NA neurons, and/or the anterior hypothalamus (AH), and/or the central nucleus of the amygdala (CEA). On the other hand, exhaustive evidence supports the positive correlation between NSA with both the (A5)-NA and/or the MR-5HT firing rate. Conversely, the (A6)-NA and the DR-5HT neurons correlated negatively with NSA, which is positively correlated with diastolic blood pressure (DBP). This parameter but not systolic blood pressure (SBP) is constantly raised in patients affected by EH. Other findings have demonstrated an antagonism between (A6)-NA and MR5HT axons at the CEA and AH areas. Predominance of the serotonergic vs noradrenergic axons occurs at both areas in spontaneously hypertensive rats (SHR) as well as EH patients. This effect is transmitted from the CEA to the BNST. Corticotropin releasing hormone (CRH) cells located at the BNST send excitatory axons to the (A5)-NA which triggers excitation at lumbar sympathetic spinal neurons. This effect is mediated by glutamate axons. Hyperactivity of the (A5)-NA neurons provokes inhibition of both (A6)-NA pontine and C1-Ad medullary neurons, both of which are crowded by alpha-2 presynaptic inhibitory receptors. In addition to the above, hyperactivated neural sympathetic activity registered during the MR-5HT + (A5)-NA over DR-5HT + (A6)-NA predominance is responsible for the inhibition of cortisol secretion which is also registered in these circumstances. This hormone crosses the blood brain barrier (BBB) and excites DR-5HT but not MR-5HT neurons. This phenomenon explains the hypocorticalism also registered in EH patients.

CNS Circuitry & Essential Hypertension

Dorsal Raphe Serotonergic Nucleus and Essential Hypertension This serotonergic nucleus innervates cortical, striatal, limbic, and hippocampal regions. In addition, the DR-5HT nucleus interchange axons with NA, DA, Ad and 5-HT nuclei located at the pontine and medullary areas. Although DR interchanges inhibitory axons with the MR-5HT nucleus, this latter exerts a greater effect on the activity of the former because the DR is a compact nucleus of serotonergic neurons whereas the 5HT neurons integrating the MR nucleus are dispersed throughout the midline pontine and suprapontine areas. Anatomical plus physiological and pharmacological evidences support the positive correlation between the MRbut not DR-5HT activity with EH syndrome (Lechin et al., 2006a). Our research studies and those from other authors leaded us to consider that a MR-5HT predominance over the DR5HT system underlies EH pathophysíology. For instance, the (A6)-NA neurons are negatively correlated with EH and in addition, axons arising from this nucleus excite DR-5HT neurons throughout alpha-1 postsynaptic receptors, located at these neurons. Conversely, a bulk of physiological, neuropharmacological and behavioral data demonstrated that MR5HT neurons antagonize both (A6)-NA and DR-5HT neurons (Lechin et al., 2006a). Furthermore, anatomical and physiological data support the postulation of a MR-5HT plus (A5)-NA positive correlation which would underlie EH. Experimental data dealing with the above will be presented further. The DR vs MR antagonism has been widely discussed in a recently published review article (Lechin et al., 2006a). In this article we presented exhaustive anatomical, physiological, clinical and neuropharmacological evidence supporting this hypothesis. Now, in the present article, we only will point out some significant data and findings emanated from hundreds of research papers which afford maximal support to our postulation that MR-5HT overactivity + DR-5HT hypoactivity underlie EH.

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MR serotonergic neurons (Lechin et al., 2006a, Ogawa et al., 1979). The above anatomical plus physiological interactions are consistent with findings showing that LC-NA axons excite and inhibit the DR but not the MR serotonergic neurons by acting at alpha-1 and alpha-2 receptors, respectively. In addition, serotonergic axons arising from both DR and MR nuclei are able to inhibit LC-NA neurons by acting at 5HT-2 receptors located at this nucleus. Finally, serotonin released from MR-5HT axons inhibits DR-5HT neurons, which is a compact nucleus crowned by 5HT-2 receptors. Conversely, this 5HT-induced inhibition is not physiologically significant at the MR-5HT nucleus (Celada et al., 2001). According to all the above, it is possible to understand the great physiological antagonism demonstrated between DR and MR serotonergic circuits. This antagonism is supported by other additional anatomical and physiological findings. For instance, DR and MR axons innervate complementary, non-overlapping CNS areas which are responsible for different and even opposite functions. Furthermore, whereas LC-NA neurons cooperate with DR-5HT neurons at both presynaptic and postsynaptic levels, a LC-NA vs MR-5HT physiological antagonism is demonstrated between both nuclei at postsynaptic areas. For instance, NA released from LC-axons at the dorsal hippocampus antagonizes the effect triggered by serotonin released from MR-5HT axons at this level, by acting at alpha-1 postsynaptic receptors located at this structure. This hippocampal area does not receive DR but MR serotonergic axons. Similar antagonism between LC-NA and MR-5HT drives have been demonstrated at the CEA and the anterior hypothalamic area, both structures do not receive axons from the DR-5HT nucleus, and in addition, are greatly involved into the circuitry responsible for EH (Amaral et al., 2003; Funakoshi et al., 2000; Salome et al., 2001; Sanchez et al., 2003; Vertes et al., 1999).

The DR-(5HT) nucleus has been exhaustively investigated in order to try to understand its role into the patophysiological mechanisms underlying cardiovascular disorders. In addition, a great bulk of research studies has been devoted to investigate which is the true role of this nucleus and the MR5HT nucleus, not only dealing with cardiovascular physiological mechanisms but also with psychological disturbances. Because serotonergic neurons are compacted into the DR and dispersed into the MR nucleus, the inhibitory effects exerted throughout 5HT-1A autoreceptors located at the somatodendritic area are notorious at the DR-5HT nucleus but negligible at the MR-5HT nucleus (Lechin et al., 2006a).

Dorsal raphe sends axons to several hypothalamic nuclei including the PVN, nucleus arcuate and ventromedial area, all of which are included into the stress circuitry. Serotonin released at these nuclei relay drives to posterior hypothalamus and the median eminence. Serotonin released at the former hypothalamic area contributes with the NA released at this level to the triggering of the excitatory drives responsible for adrenomedullary excitation that enhances peripheral adrenal sympathetic activity. This branch of the peripheral sympathetic system is inter-connected with the adrenaline C1 + noradrenaline (A1 and A2) + serotonin (raphe magnus, raphe obscurus and raphe pallidus) + the parasympathetic medullary structures (n. ambiguus, NTS, AP, and dorsal motor vagal nuclei) all of which are responsible for the acute changes of cardiovascular parameters. However, evidence have demonstrated that this circuitry plays a secondary but not a primary role into the mechanisms underlying EH (Funakoshi et al., 2000).

Other findings show that noradrenergic (alpha-2) inhibitory receptors have also been demonstrated at the DR but not MR serotonergic neurons. These receptors are located at GABA-neurons which crowned the DR but not the MR nucleus. Noradrenaline released from (A6)-NA axons, excites GABA neurons (crowded by alpha-2 receptors). The release of GABA inhibits DR-5HT neurons. Finally, alpha-1 excitatory receptors are also found at the DR-5HT neurons. This type of receptors does not play a physiological role at the

Other findings showed that the hypothalamic PVN sends axons to the median eminence which connects the central to peripheral stress cascade integrated by CRH, ACTH and corticosterone released from the adrenal glands. Both the C1-Ad medullary nuclei plus the CRH—ACTH—corticosterone drives constitute the two branches of the peripheral stress cascade which display both acute agonist and chronic antagonistic effects. With respect to this, it should be remembered that both neural and adrenal released catechola-

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mines antagonize and inhibit the release of cortisol. Despite of the above, exhausted evidence demonstrated that catecholamines secreted during the stress cascade at this level trigger significant cardiovascular effects that are not responsible for the sustained DBP rise registered in EH (Beaulieu et al., 1986). Corticosterone released from the adrenal glands crosses the BBB and excites DR but not MR serotonergic neurons which becomes overactivated and provokes additional enhancement of the CRH—ACTH—corticosterone cascade. Prolongation of this disorder leads to exhaustion of DR-5HT but not MR-5HT neurons thus, predominance of the latter occurs during chronic stress situation. A bulk of information dealing with this issue has been quoted and affords support for the postulation that this pathophysiological mechanism should underlies in many diseases, like endogenous depression (Beaulieu et al., 1986; Lechin et al., 2006a,), TH-1 autoimmune diseases and EH, all of which frequently show exhaustion of adrenal glands activity plus disinhibition of the thymus gland secondary to the lowered levels of circulating cortisol (Herman et al., 2005; Huether 1996; Huether et al., 1996; Lovick 1993; Robinson et al., 1983). Summarizing all the above, DR-5HT hyperactivity is able to trigger labile hypertensive syndromes by the enhancement of the acute stress mechanisms but this type of physiological disorder travels in the opposite address of that which leads to the disorder underlying EH. Median Raphe Serotonergic Circuitry and Essential Hypertension This serotonergic nucleus innervates complementary CNS areas not reached by DR-5HT axons. Special mention should be addressed to the medial septum, dorsal hippocampus, accumbens core, anterior hypothalamus, and the CEA. Although MR-5HT axons share with DR-5HT axons some hippocampal areas (dorsomedial and anterolateral) as well as the hypothalamic arcuate nucleus, MR-5HT axons innervate the medial preoptic, suprachiasmatic and anterior hypothalamic nuclei, exclusively (Vertes et al., 1999). This anatomical dissociation fits well with some specific and separated functions exerted by both serotonergic drives. For instance, median raphe axons innervate most if not all noradrenergic, dopaminergic, acetylcholinergic, and adrenergic nuclei located at the pontine and medullary regions. However, considering that MR-5HT neurons are dispersed throughout the midline of the pontine and supra-pontine midbrain it is not submitted to perpendicular impacts which may trigger black/white responses; in addition, MR-5HT neurons are not surrounded by GABA inhibitory neurons like the DR-5HT nucleus (Tao and Auerbach, 2003). Conversely, MR-5HT neurons are submitted to the excitatory influence of glutamate neurons. This glutamatergic innervation is not present at the DR-5HT nucleus. These anatomical and physiological differences fit well with the dissociated and frequently opposite activities displayed by both serotonergic nuclei. Neuropharmacological findings showed that although 5HT-1A agonists are able to inhibit MR-5HT neurons during experimental (pharmacological) studies, systemic administration of these types of drugs does not provoke the inhibitory effects demonstrated with DR-5HT neurons. Conversely, systemic administration of 5HT-1BD agonists triggers inhibition of the MR-5HT rather than DR-5HT circuitry. With respect to this, considering that 5HT-1BD receptors are also located at

Lechin and van der Dijs

the terminal axons of serotonergic neurons, these, rather than somatodendritic autoreceptors should be responsible for the inhibitory effects triggered by the 5HT-1BD neuropharmacological agonists. Furthermore, considering that DR and MR interchange axons, it is logically to infer that they display dissociated and/or opposite activities (Lechin et al., 2006a). Other anatomical plus physiological data demonstrate that DR but not MR serotonergic neurons receive excitatory axons from dopaminergic (DA) neurons (A8+A9 nuclei). This DA drives explain the positive correlation of DR-5HT but not MR-5HT neurons with the motility behavior (Trulson and Frederickson, 1987). These findings are consistent with the well known fact that exercise activity provokes exhaustion of DR but not MR serotonergic neurons. Conversely, restraint stress activates and provokes exhaustion of the MR but not DR serotonergic neurons. Other stimuli like photic and acoustic excite and are able to provoke exhaustion of MR but not DR neurons. The above mentioned data together with the following finding would help to understand the different roles played by both serotonergic systems in many pathophysiological mechanisms (Lechin et al., 2006a). Although MR-5HT neurons are also involved into the stress mechanisms, these neurons are excited by different type of stressors that those which affect DR-5HT neurons. Evenmore, the stressors able to excite MR-5HT neurons are different to those responsible for the activation of DR-5HT neurons. With respect to this, we will attempt to summarize the CNS circuitry involved in the stress provoked by those stimuli which are able to increase the firing rate of MR-5HT neurons. Considering that motility behavior is positively and negatively correlated with the firing activity of the LC-NA + DR5HT and MR-5HT neurons, respectively, we can understand that the two former nuclei but not the latter showed increased firing activity at this period. This phenomenon fits well with the known fact that (A6)-NA and DR-5HT display a close positive functional correlation. Conversely, neither NA nor 5HT axons arising from these nuclei are able to excite MR5HT neurons, furthermore, the NA + 5HT drives arising from them travel to the hypothalamic PVN nucleus throughout direct projections. Conversely, stressors acting at the MR-5HT neurons used a different circuitry throughout the CEA and the BNST and anterior hypothalamus (Bauman and Amaral, 2005; Cryan et al., 2002; Dampney et al., 2005; Feldman et al., 1990; Koulu et al., 1986a; Makino et al., 1999; Sanchez et al., 2003; Vitale et al., 2005). This is the circuitry involved into the restraint, photic, sound, and psychological induced stress. This pathway also reaches the PVN but funneling by the above mentioned circuitry and reaching the preoptic area which is exclusively innervated by MR but not DR serotonergic axons. This hypothalamic nucleus is maximally involved in EH (spontaneously hypertensive rats = SHR) which is the adequate model of human EH (Benarroch et al., 1981; Horiuchi et al., 2005; Kuhn et al., 1980; McCall and Humphrey, 1982; McCall 1984; Robinson 1982; Tsukamoto et al., 2000). Table 1. Considering that the CEA nucleus receives axons from the MR-5HT and the A6 + A5 NA neurons but not from the DR-5HT neurons (Feldman et al., 1990), the balance be-

CNS Circuitry & Essential Hypertension

Table 1.

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Two Types of CNS & Peripheral Stress Cascades Underlying Two Types of Hypertensive Syndromes

Motility Hyperactivity and Anxiety Stress

Acoustic, Photic, Psychologic and Restraint Stress







(A6)-NA

Dorsal Raphe (5HT Neurons)

Median Raphe (5HT Neurons)







Paraventricular Nucleus (PVN) 

Central Amygdalar Nucleus (CEA)





Posterior Hypothalamus

Median Eminence (CRH)





C1-Ad

Hypophysis (ACTH)





Cervical + Thoracic Sympathetic Spinal Neurons

Cortical Adrenal Glands

Median Eminence (CRH)

Lumbar Sympathetic Spinal Neurons









Adrenal Glands

Cortisol

ACTH

 Adrenal Sympathetic Hyperactivity

Bed Nucleus Stria Terminalis (BNST)  PVN

›—

 Anterior Hypothalamus

←



(A5)-NA 

 Cortical Adrenal Inhibition



›—

Neural Sympathetic Hyperactivity





Non-Essential Hypertension

Essential Hypertension

Raised levels of cortisol and adrenaline are registered in the plasma of mammals submitted to the motility and/or anxiety stress (Type I stress). Conversely, raised levels of noradrenaline/adrenaline plasma ratio are registered in mammals stressed through acoustic, photic, psychological and restraint stress (Type II stress). Although both type of stressors trigger hypercortisolemia, this parameter is suppressed by the administration of dexamethasone in Type I stress but not in Type II stress. These findings are consistent with the facts showing that the DR-5HT but not the MR-5HT is crowded with cortisol receptors which are up-regulated in the Type I but not in the Type II stress. The above postulation is reinforced by facts showing that the dexamethsone suppresses cortisol plasma level in non-essential hypertensive patients but not in essential hypertensive patients. (Lechin et al., 1986, 1987, 1993, 1996c, 2004a, 2006a).

tween both neurotransmitters would play a primordial role in the pathophysiology of EH. Evenmore, the fact that the DR5HT axons bridle the LC-NA and in addition display antagonistic effects to the MR-5HT, predominance of this latter would favor BP rise. With respect to this, it should be remembered that SHR have a reduced number of LC-NA neurons (Dabsys et al., 1988; Funakoshi et al., 2000; Kawamura et al., 1978). In addition to the above, it has been exhaustively shown that EH is negatively correlated with the number and firing activity of the LC-NA nucleus (Ogawa 1978). Furthermore, considering that both (A6)-NA and (A5)-NA nuclei interchange inhibitory axons oblige us to infer that a predominance of the latter should underlie into any LC-NA deficient disorder. In addition to all the above, the relevance of the NA vs 5-HT circuitries interacting at the CEA is reinforced by the demonstrated fact that destruction of this amygdalar nucleus provokes definite lowering of BP (Folkow et al., 1982; Sun 1995). Other findings demonstrated that psychological stress does not use the LC-NA + DR-5HT + PVN circuitry (Huether et al., 1996; Huether 1996) but the MR-5HT + CEA + BNST + PVN circuitry. These findings are consistent with others demonstrating that the depressive profile is present in EH patients. With respect to this, it has been definitely demonstrated that MR over DR serotonergic predominance un-

derlies this psychological disorder (Dilsaver and Coffman, 1988; Lechin et al., 1985, 1995; Matthews et al., 2005; Simonsick et al., 1995). Stress and Essential Hypertension The activation of the CNS stress mechanisms depending on environmental challenges triggers concerted activation of all three major peripheral effector systems: the neural sympathetic system, the adrenomedullary sympathetic system and the adrenocortical system. Although catecholamines do not cross the BBB, corticosteroids are able to directly enter the brain and to interact with corticosteroid receptors expressed by neurons. The message conveyed to the brain by the stress-induced increase of circulating glucocorticoids is characterized by two important features: 1) there is a considerable time lapse between the onset of stress and the elevation of glucocorticoid levels in the brain. In addition, the effects of corticosteroids in the brain are characterized by a slow onset and long duration. 2) Corticosteroids can bind to two types of intracellular receptors: Type 1, high affinity (mineralocorticoid) receptors and Type II, low affinity (glucocorticoid) receptors. With respect to this, glucocorticoid receptors are located at the DR-5HT neurons. Both corticosterone and CRH are able to excite this serotonergic nucleus until provokes its exhaustion. This phenomenon is consistent

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with the predominance of MR-5HT over the DR-5HT system registered during chronic stress and depression. The above is explained by the fact showing that the latter but not the former is crowded with both CRH + corticosterone receptors. Conversely, glucocorticoid receptors are located at the postsynaptic MR-5HT projection areas (dorsal hippocampus) but not at the DR-5HT projection areas (ventral hippocampus). In addition to the above, it has been demonstrated that glucocorticoids inhibit the activity of NA neurons. This effect is reflected by the up-regulation of presynaptic alpha-2 receptors located at the LC-NA neurons. Both the inhibition of LC-NA plus the excitement of DR-5HT activities is consistent with the stress activity exerted by glucocorticoids. The excitation of the LC-NA plus the DR-5HT activities is consistent with the increase of both the catecholamines and cortisol plasma levels, registered during acute stress periods. The rise of catecholamines depends on the C1-Ad overexcitation which arises from the LC-NA nucleus, whereas the DR-5HT is responsible for the increase of plasma corticosterone. However prolongation of this (A6)-NA + DR-5HT + C1-Ad overactivity, registered during acute stress may lead to two different disorders: Uncoping stress, and Coping stress. Uncopings stress is the physiological disorder responsible for the excessive, maximal, increase of both CRT and cathecolamines plasma levels. Adrenaline but not noradrenaline predominance is registered because catecholamines arise from the adrenal glands but not from the sympathetic nerves; whereas DR-5HT overactivity is responsible for the high cortisol plasma level. Taking into account that cortisol crosses the BBB and triggers inhibition of the (A6)-NA plus excitation of the DR-5HT neurons, it may explain the maximal plasma values of adrenaline and cortisol registered in these circumstances. This peripheral profile reflects the absolute predominance of the DR-5HT + C1-Ad over the MR5HT + (A5)-NA. Coping stress is registered in mammals well adapted to chronic stress. This CNS + peripheral profile depends on the relative predominance of the (A5)-NA + MR-5HT neurons over the (A6)-NA + DR-5HT nuclei. At peripheral level, enhanced NA and reduced cortisol plasma levels are registered in these circumstances. Prolongation plus accentuation of this CNS + peripheral neuroautonomic disorder underlies both endogenous depression and essential hypertension syndromes. This (A5)-NA + MR-5HT absolute predominance fits well with the alexithymic profile presented by both type of patients. The above findings are consistent with the glucocorticoid hypersensitivity demonstrated in essential hypertensive patients at peripheral levels (Beaulieu et al., 1986; Fairchild et al., 2003; Weitemier and Ryabinin, 2006; Wirtz et al., 2004). The above discussion is consistent with the well demonstrated fact showing that the inhibition of the LCNA neuronal activity is followed by the reduction of 5HT release from the DR-5HT axons and a compensatory increase of serotonin from MR-5HT axons. Disinhibition of these latter neurons from the weak bridling effects arising from DR-5HT axons fits well with all the above (Lechin et al., 2006a; Saavedra et al., 1976). Other findings add to the understanding of the complex CNS circuitry involved in the possible mechanisms that associate stress to the pathophysiology of EH. For instance,

Lechin and van der Dijs

stimulation of the CNS noradrenergic neurons after the acute immobilization stress (which activates MR but not DR serotonergic neurons) is most pronounced in the ventrolateral ponto-medullary NA cell groups (A5) than the pontine (A6)NA neurons. These findings are consistent with the demonstration that NA release occurs first in subcortical (A5-NA axons) than pre-frontal cortical level (innervated by A6axons) (Matthews et al., 2002). Noradrenaline is greatly released also at the CEA nucleus (A5 plus A6 axons) (Byrum and Guyenet, 1987), which is greatly involved in the mechanisms underlying psychological stress and receives heavy innervation from MR-5HT axons but not DR-5HT axons (Cameron et al., 2004; Huether et al., 1996; Huether 1996; Makino et al., 1999). The role played by the MR-5HT—CEA circuitry in the EH is further understood on the light of some experimental findings. For instance, stimulation of the CEA induces behavioral arousal, increases heart rate, BP and respiratory rate as well as elevates plasma catecholamines. Furthermore, lesions of the CEA block the ACTH and cortisol responses to psychological stressors. These facts are consistent with others showing that the CEA is rich in CRH-containing neurons which project to the hypothalamus and to the brain stem (Gray et al., 1989). In addition, extensive descending pathway originates within the CEA and terminates within the midbrain, pons and medulla oblongata including the catecholaminergic and serotonergic nuclei. Along with these efferences the CEA is believed to coordinate the behavioral, autonomic and endocrine aspects of the stress response (Dabsys et al., 1988; Fenik et al., 2002; Gray et al., 1989; Saha et al., 2005). Other findings showed that descending CRH-containing fibers especially from CEA project to the medullary NA cell groups (A5, A2 and A1), their release of CRH cause activation of NA firing. During prolonged or intense activation, the NA efferences back to the CEA and provoke further release of CRH (Fenik et al., 2002). This positive feedback loop escalates the release of both NA and CRH in the course of the CNS stress response. Considering all the above, it is possible to understand that the CEA and the (A5)-NA pontine nucleus and not the LC-NA nucleus are greatly involved in EH. The above findings receive additional support from others showing that electrical stimulation of the CEA elicits a rise in DBP, the main and most important parameter increased in EH (Gauthier 1981; Salome et al., 2001). Other findings showed that amigdaloid axons reach the PVN of the hypothalamus by two routes: 1) via the stria terminalis and 2) directly through the substantia innominata and/or over the optic tract (Lovick 1993). The former axons arrive at the anterior part (which receives axons from the MR but not the DR serotonergic nucleus) whereas the latter axons arrive to the posterior part of the PVN. The former drive is richer than the latter (Herman et al., 2005). Bilateral lesions of the amygdala inhibit adrenocortical responses to stress-induced somatosensory and olphactory stimuli. Other finding demonstrated that destruction of the CEA attenuates the secretion of ACTH after adrenalectomy. Furthermore, lesions localized at the CEA dramatically reduce ACTH response to immobilization stress, which excites

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MR but not DR serotonergic neurons, and in addition, increased serotonergic activity at the CEA (Beaulieu et al., 1986; Cameron et al., 2004; Corley et al., 2002; Herman et al., 2005). Other findings demonstrated that destruction of the CEA is responsible for blocking of ACTH hypersecretion observed after adrenalectomy (disappearance of cortisol). This effect should be associated with the destruction of LC-NA axons which are located at this nucleus and exert antagonistic activity to MR-5HT axons arriving to this area. This phenomenon is consistent with the registered NA-CRH-ACTH stress cascade which depends on CEA-PVN connection that is also responsible for the CRH-induced vasopressin, angiotensin, oxytocin and other neuropeptide secretions (Beaulieu et al., 1986). The CEA also projects heavily upon central regions of the lateral BNST which in turn projects upon the CRH-containing regions of the PVN, the NTS and the parabrachial nuclei. Lesions of this medullary projecting component of the ventro-amygdalofugal pathway reduced ACTH hypersecretion caused by adrenalectomy. Finally, lesions of the CEA reduce the CRH content of the median eminence. This effect would depend on the amygdaloid projections upon CRH-containing cell regions of the PVN, because there is not a direct connection between CEA and the median eminence (Beaulieu et al., 1986; Herman et al., 2005; Makino et al., 1999). The CEA is greatly involved in the circuitry responsible for BP regulation, since destruction of this nucleus triggers BP reduction in SHR (Corley et al., 2002; Gray et al., 1989; Lovick 1993; Sun 1995; Zimmermann and Ganong, 1980). Considering that MR but nor DR sends axons to the CEA the former but not the latter nucleus should be considered as a link of the circuitry responsible for this syndrome. Hyperactivity of the MR-5HT neurons would antagonize LC-NA neurons as well as axons at the CEA and favors the hypoactivity of these neurons always demonstrated in hypertensive rats. These findings allow understand that whereas DR-5HT exerts a direct inhibitory influence on the LC-NA activity, MR-5HT axons antagonize the LC-NA axons at the CEA nucleus. Furthermore, considering that both serotonergic nuclei display antagonistic activities, the MR but not the DR5HT predominance would underlie into the EH mechanisms. Additional information arises from facts showing that (A6)-NA neurons send excitatory axons to the DR-5HT but not to the MR-5HT neurons. In turn, DR but not MR sends inhibitory axons to the (A6)-NA neurons. With respect to this, Kaehler et al. (1999) demonstrated that the release of serotonin at the (A6)-NA nucleus evoked by NA infusion into the DR-5HT nucleus was more pronounced in normal than SHR. This phenomenon is consistent with the demonstration that the DR-5HT neurons of SHR showed a greater than normal excitatory response. This effect would depend on the up-regulation of alpha-1 receptors, which crowd DR5HT neurons. This phenomenon would be secondary to the diminished release from NA axons at the DR-5HT neurons. According to the above, it seems obvious that the diminished (A6)-NA activity present in SHR would be secondary to the inhibition triggered by the DR-5HT axons. Other findings by De Souza and van Loon (1986) demonstrated that the restraint stress (which excites MR-5HT but

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not DR-5HT neurons) increased the 5-HIAA (5-hydroxiindole acetic acid, a serotonin metabolite) concentration at the anterior hypothalamic nucleus (innervated by MR but not DR serotonergic axons) (Hagiwara et al., 2005). The NA levels were reduced at this nucleus during this experimental study. These findings are consistent with the well known fact that MR-5HT axons are able to reduce the firing rate of (A6)-NA neurons (Lechin et al., 2002b; Saavedra et al., 1976). Conversely, the (A5)-NA neurons were excited during this experimental design, as revealed by the increase of NA at the anterior hypothalamic area (innervated by this nucleus). On the contrary, the NA levels were reduced at the posterior hypothalamus which receives axons from the (A6)NA neurons, preferentially. These experimental findings reinforce the positive physiological correlation between the MR-5HT and the (A5)-NA neurons. The fact that the NA but not the Ad plasma level were increased during this experimental design give additional support to the postulation that this is the CNS disorder underlying both neural sympathetic activity and EH. Other experimental studies by Tsukamoto et al. (2000) demonstrated that the NTS, which is included amongst the parasympathetic motor medullary complex is hyperresponssive to the serotonin directly injected at this level. With respect to this, the NTS is crowded with 5HT-3 and 5HT-4 receptors which are excited by DR-5HT axons. This 5-HT + ACh circuitry is responsible for the BP fall triggered by serotonin at NTS. The hyperresponssiveness to 5HT registered in SHR is consistent with a deficit of DR-5HT firing activity, which would favor the hypothesis that the hypertensive syndrome should be associated with MR-5HT predominance. Other experimental designs demonstrated that the anterior hypothalamic nucleus is greatly involved into the circuitry responsible for neurogenic hypertension. With respect to this, Gauthier et al., (1981) demonstrated that electrical stimulation of this area caused DBP rise + plasma NA but not Ad increase (which depends on neural sympathetic activity). Furthermore, the fact that MR-5HT but not DR-5HT axons innervate this hypothalamic area reinforces our postulation of a MR over DR serotonergic predominance underlying this syndrome. Additional evidences arise from findings by Smits et al. (1978) who demonstrated that electric stimulation of the MR but not the DR serotonergic neurons triggers DBP rise. Additional information arises from findings that fit well with our postulation. For instance Benarroch et al. (1981) demonstrated that the injection of angiotensin II into the anterior hypothalamus triggers DBP increase. These authors demonstrated also that (A5)-NA + MR-5HT and (A6)-NA + DR-5HT circuits are positively and negatively correlated with neurogenic hypertension, respectively. Other studies afford additional support to our hypothesis, for instance, findings by Gurtu et al. (1984) demonstrated that the stimulation of the (A6)-NA plus DR-5HT circuit triggers both systolic BP + heart rate increases throughout the release of adrenal glands catecholamines. This effect is mediated by the activation of the hypothalamic (PVN) + adrenal glands cascade. Whereas the excitation of the (A5)-NA + MR-5HT binomial provokes DBP increase throughout the activation of the medullary (thoracic plus lumbar) sympathetic pregan-

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glionic neurons, responsible for the enhancement of neural sympathetic activity. In addition to the above, studies by Korner et al. (1987) demonstrated that whereas pressor effect excites the (A6)-NA neurons which induces depressor response, hypotension excites (A5)-NA neurons, which induces a pressor response. Other findings by Murase et al. (1994) showed that the peptide neurotensin, whose activity is positively associated with BP rises, inhibits the cell firing of the (A6)-NA neurons. This effect is on line with others by Young et al. (1978) who demonstrated that neurotensin triggers inhibition of the spontaneous as well as glutamate-stimulated (A6)-NA activity. Conversely, neurotensin favors the (A5)-NA firing rate. At the peripheral levels, it has been exhaustively demonstrated that neurogenic SHR and humans show enhancement of the NA/Ad plasma ratio. These findings are consistent with neural sympathetic over adrenal sympathetic predominance. A bulk of evidence supports the above findings (Lechin et al., 1989d, 1991, 1993, 1996b, 2004a). Other research studies give additional support to our postulation that the (A5)-NA neurons are positively correlated with EH. For instance, CNS administered angiotensin II excites these neurons and in addition increase DBP (Sumners and Phillips, 1983). Furthermore, this peptide is increased in the cerebrospinal fluid of both SHR and EH patients (Basso et al., 1989). Some additional evidence showed that DR-5HT and MR5HT neurons are negatively and positively correlated with neurogenic hypertension, respectively. For instance, Zimmerman and Ganong (1980) demonstrated that stimulation of the CNS-5HT pathways excites the renal nerves that trigger renin secretion. This effect is not mediated by the sympathetic nerves. In addition, renin release is positively and negatively correlated with the MR and DR serotonergic activity, respectively. With respect to this, van de Kar et al. (1984) showed that stress triggers prolactin + renin plasma increases. However, electrolytic lesions in the MR-5HT did not affect prolactin increase but interfered with renin effect. With respect to this, other findings by van de Kar et al. (1984) demonstrated that both MR-5HT and (A5)-NA neurons are responsible for the renin secretion. Finally, other studies showed that angiotensin II and renin are increased in the cerebrospinal fluid of EH patients. The above studies are on line with other by Lorenz and van de Kar (1987) who demonstrated that renin is secreted by the juxtaglomerular cells of the kidney and is the rate-limiting enzyme for the synthesis of angiotensin II, a peptide important for the regulation of BP and aldosterone secretion. Finally, the depletion of NA in the anterior hypothalamic nucleus, induced by 6OHDA injected into the ventral pons, triggers neurogenic hypertension in rats. This effect is attributed to the removal of the NA tonic depressor activity, depending on the (A6)NA axons. The primary role played by MR-5HT neurons in neurogenic hypertension receives additional support from findings by Lawler et al. (1985) who demonstrated that SHR showed significantly larger DBP rise following the onset of the restraint stress period, than that registered in normal rats. These findings are consistent with the well known fact that this type of stressor excites the MR but not the DR seroton-

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ergic neurons. The above findings receive additional support from others by Corley et al. (2002) showing that the stressinduced activation of MR-5HT neurons in rats is potentiated by the neurotensin antagonist SR48692, which inhibits the DR-5HT but not the MR-5HT. These phenomena are consistent with the facts showing that the DR-5HT but not the MR5HT neurons are inhibited by presynaptic GABA neurons (Lechin et al., 1989c; Tao and Auerbach, 2003). Other experimental studies afford additional support to the MR over DR serotonergic predominance underlying EH. With respect to this, it has been shown that DR-5HT excitation enhances Ad plasma level whereas MR-5HT excitation provokes NA plasma increase. This latter but not the former is found raised in EH patients (Christensen 1983; Lechin et al., 2005; Robinson 1982). Both the CEA and the anterior hypothalamus play a primordial role into the circuitries underlying BP regulation. Both CNS structures are innervated by MR but not DR serotonergic axons. Serotonin released at these areas antagonizes the depressor effect triggered by NA release from (A6)-NA axons. This antagonism between those nuclei occurs during all type of stress involving MR-5HT but not DR-5HT axons, like restraint, photic, loudness and psychological stimuli. This is also consistent with the demonstrated fact that EH patients present a depressive rather than an anxious psychological profile. Summarizing all the above, exhaustive evidence support the postulation that whereas non-EH is associated with the anxiety and motility behavioral CNS circuitry: (A6)-NA + DR-5HT + PVN + C1-Ad + posterior hypothalamus + adrenal glands stress cascade; EH would be referred to the (A5)NA + MR-5HT + CEA + BNST + PVN + anterior hypothalamus + spinal lumbar sympathetic neurons circuitry. Both CNS circuitries would be associated with the adrenal and neural sympathetic activity, respectively. These findings receive additional support from the well demonstrated anatomical + physiological + neuropharmacological antagonism relaying at the bottom of these circuitry. The above postulated CNS-circuitry underlying both types of hypertension disorders receive additional support from a great deal of experimental evidence. For instance, Oishi et al. (1979) demonstrated that the (A6)-NA axons play an inhibitory role in the electrical activity of the CEA, which is antagonized by MR-5HT axons. In addition, Gauthier et al. (1981) demonstrated that electrical stimulation of the anterior hypothalamus causes DBP increase which depends on neural-mediated noradrenaline release from sympathetic vasoconstrictor fibers. Furthermore, Salome et al. (2001) showed that the CEA sends inhibitory axons to the C1-Ad medullary nuclei (responsible for adrenal glands secretion) but not to the (A5)-NA nucleus responsible for neural sympathetic activity. Finally, Dabsys et al. (1988) demonstrated that NA depletion of the CEA (innervated by A6 axons, mainly) triggers an increase in specific angiotensin converting enzyme and neurogenic hypertension, in rats. CONCLUSION Our studies as well as those from others support the concept that EH depends on the hyperactivity of the neural sympathetic but not the adrenal sympathetic peripheral system. In addition, we quoted evidence demonstrating that the CNS

CNS Circuitry & Essential Hypertension

circuitry responsible for the neural sympathetic hyperactivity, would depend on the (A5)-NA + MR-5HT over the (A6)-NA + DR-5HT predominance. The whole circuitry of the former would include the CEA, the bed nucleus of the stria terminalis, the anterior hypothalamus and lumbar sympathetic spinal neurons. This circuitry would predominate over that responsible for adrenal sympathetic activity, which includes the PVN + posterior hypothalamic nuclei, the C1Ad medullary nuclei, the raphe pallidus (serotonergic) medullary nucleus and the cervical + thoracic preganglionic spinal sympathetic neurons. Neuropharmacological manipulations addressed to revert this CNS disorder open a new way in the therapy of EH. REFERENCES Adell, A, Artigas, F. (1999) Regulation of the release of 5hydroxytryptamine in the median raphe nucleus of the rat by catecholaminergic afferents. Eur J Neurosci 11: 2305-2311. Agren, H, Koulu, M, Saavedra, JM, Potter, WZ, Linnoila, M. (1986) Circadian covariation of norepinephrine and serotonin in the locus coeruleus and dorsal raphe nucleus in the rat. Brain Res 397: 353-358. Amaral, DG, Behniea, H, Kelly, JL. (2003) Topographic organization of projections from the amygdala to the visual cortex in the macaque monkey. Neuroscience 118: 1099-1120. Anderson, DJ, Puttfarcken, PS, Jacobs, I, Faltynek, C. (2000) Assessment of nicotinic acetylcholine receptor-mediated release of [(3)H]norepinephrine from rat brain slices using a new 96-well format assay. Neuropharmacology 39: 2663-2672. Astier, B, Kitahama, K, Denoroy, L, Berod, A, Jouvet, M, Renaud, B. (1986) Biochemical evidence for an interaction between adrenaline and noradrenaline neurons in the rat brainstem. Brain Res 397: 333-340. Astier, B, Van Bockstaele, EJ, Aston-Jones, G, Pieribone, VA. (1990) Anatomical evidence for multiple pathways leading from the rostral ventrolateral medulla (nucleus paragigantocellularis) to the locus coeruleus in rat. Neurosci Lett 118: 141-146. Baraban, JM, Aghajanian, GK. (1981) Noradrenergic innervation of serotonergic neurons in the dorsal raphe: demonstration by electron microscopic autoradiography. Brain Res 204: 1-11. Basso, N, Kurnjek, ML, Mikulic, L, Ruiz, P, Canata, MA, Taquini, AC. (1989) The central and peripheral renin-angiotensin and noradrenergic systems in the spontaneous hypertensive rats (SHR). Arch Int Physiol Biochim 97: 53-58. Bauman, MD, Amaral, DG (2005) The distribution of serotonergic fibers in the macaque monkey amygdala: an immunohistochemical study using antisera to 5-hydroxytryptamine. Neuroscience 136: 193-203. Beaulieu, S, Di Paolo, T, Barden, N. (1986) Control of ACTH secretion by the central nucleus of the amygdala: implication of the serotoninergic system and its relevance to the glucocorticoid delayed negative feedback mechanism. Neuroendocrinology 44: 247-254. Benarroch, E E, Balda, MS, Finkielman, S, Nahmod, VE. (1983) Neurogenic hypertension after depletion of norepinephrine in anterior hypothalamus induced by 6-hydroxydopamine administration into the ventral pons: role of serotonin. Neuropharmacology 22: 29-34. Benarroch, EE, Pirola, CJ, Alvarez, AL, Nahmod, VE. (1981) Serotonergic and noradrenergic mechanisms involved in the cardiovascular effects of angiotensin II injected into the anterior hypothalamic preoptic region of rats. Neuropharmacology 20: 9-13. Bhaskaran, D, Freed, CR. (1988) Changes in arterial blood pressure lead to baroreceptor-mediated changes in norepinephrine and 5-hydroxyindoleacetic acid in rat nucleus tractus solitarius. J Pharmacol Exp Ther 245: 356-363. Borsody, MK, Weiss, JM (2005) The subdiaphragmatic vagus nerves mediate activation of locus coeruleus neurons by peripherally administered microbial substances. Neuroscience 131: 235-245. Briggs, I. (1977) Excitatory responses of neurones in rat bulbar reticular formation to bulbar raphe stimulation and to iontophoretically applied 5-hydroxytryptamine, and their blockade by LSD 25. J Physiol 265: 327-340. Burchfield, SR (1979) The stress response: a new perspective. Psychosom Med 41: 661-672. Byrum, CE, Guyenet, PG. (1987) Afferent and efferent connections of the A5 noradrenergic cell group in the rat. J Comp Neurol 261: 529-542.

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