European Heart Journal (1992) 13 (Supplement A), 10-17
Central mechanisms regulating blood pressure: Circuits and transmitters J. CULMAN AND T. UNGER
Department of Pharmacology and German Institute for High Blood Pressure Research, University of Heidelberg, Germany
Introduction Adaptation of the cardiovascular system to an organism's requirements is achieved by interaction between central and peripheral regulatory mechanisms. Cardiovascular homeostasis is centrally controlled by a complex network of mechanisms involving several brain regions and neurotransmitter systems. The precise role of individual structures and agents in the central nervous system (CNS) controlling arterial blood pressure has not yet been established. Several brain regions, including the cerebral cortex and the hypothalamus, are involved in the generation of the final output to the vegetative nervous system; however, only a limited number of distinct brain nuclei play a direct role in central cardiovascular regulation. Neuroanatomical studies have revealed a dense network of interconnections between these nuclei. In the following, the organization of the central nervous system and the role of some neurotransmitter and neuropeptide systems, with regard to the regulation of blood pressure (BP) and heart rate (HR), are briefly reviewed.
NUCLEUS TRACTUS SOLITARII (NTS)
The NTS receives afferent inputs from arterial baroreceptors and chemoreceptors via the IXth and Xth cranial nerves. Central afferents derive from other regions in the medulla oblongata, the paraventricular nucleus (PVN) of the hypothalamus and amygdala1'•5|, and it is well established that NTS plays a key role in the central activation of the baroreceptor reflex. HYPOTHALAMIC NUCLEI
The paraventricular (PVN) and supraoptic nuclei (SON) represent an important site for the integration and regulation of neuroendocrine and autonomic processes'5'. The PVN receives afferent input, among others, from the ventrolateral medulla and locus coeruleus (LC), and neurons in the PVN project to the spinal cord, the parabrachial nucleus, the LC and to the dorsal vagal complex'3'6'. Electrical stimulation of these and other hypothalamic structures produce a wide range of cardiovascular effects. For instance, electrical stimulation of the posterior hypothalamus leads to a pressor response accompanied by an increase in locomotor activity17'. LIMBIC SYSTEM AND CORTEX
Brain areas involved in cardiovascular control AREAS IN THE MEDULLA OBLONGATA
Experimental evidence shows that neurotransmitter systems in the rostral part of the ventrolateral medulla (RVLM) provide a tonic excitatory drive to sympathetic preganglionic neurons'1'. Anatomical and neurophysiological studies revealed direct connections between the RVLM with a number of other brain areas which are involved in central control of the cardiovascular system. The RVLM receives direct neuronal input from the nucleus tractus solitarii (NTS), a site where the afferent neurons from the carotic sinus and aortic arch terminate'1'. The sympathoexcitatory neurons in the RVLM are under the inhibitory influence of NTS neurons'2'. The caudal parts of the ventrolateral medulla (CVLM) are also involved in central cardiovascular control. Stimulation of the CLVM produces a decrease in blood pressure (BP) and heart rate (HR)'31, and the RVLM seems to mediate the vasodepressor response elicited by stimulation of the CVLM' 34 '. 0195-668X/92/0A0010 + 08 $03.00/0
Lower brainstem cardiovascular centres are under the direct influence of the limbic system and cerebral cortex. The central amygdaloid nucleus may represent a link between the sensory cortical areas and the cardiovascular centres of the hypothalamus and brainstem. The central amygdala appears to play a role in the development of hypertension in spontaneously hypertensive rats'8'. Like the limbic system, the cerebral cortex is involved in transforming sensory inputs and emotions into cardiovascular reactions. DEFENCE REACTION
Electrical stimulation of certain hypothalamic or brainstem areas induces a typical integrated cardiovascular and behavioral reaction called a defence reaction. This reaction is characterized by an increase in BP and heart rate (HR), by vasoconstriction in the splanchnic, renal and cutaneous circulation and skeletal muscle vasodilation. The whole defence reaction pattern, which appears to be important in the cardiovascular response to stress, can be elicited after stimulation of certain areas in the hypothalamus or periaqueductal grey matter1''1. 1992 The European Society of Cardiology
Central mechanisms regulating blood pressure 11
Neurotransmitters involved in central cardiovascular control A number of classical neurotransmitters have been implicated in central cardiovascular control, among these, catecholamines and serotonin are particularly prominent. Other neurotransmitters include histamine, acetylcholine, y-aminobutyric acid (GABA) and a number of neuropeptides such as vasopressin, substance P, angiotensin II, opioid peptides, atrial natriuretic peptide (ANP) etc. These latter substances may act as classical neurotransmitters or as neuromodulators mediating the pre- and postsynaptic action of other neurotransmitters. MONOAMINES
Catecholamines Noradrenaline (NA) and adrenaline (A) cell bodies have been demonstrated in the lower brainstem. NA cell bodies are present in A1-A7 cell groups and A cell bodies in Cl and C2 cell groups'10"12'. The Al and Cl cell groups lie in the ventrolateral part of the medulla, A2 and C2 cover NTS territory and the dorsal motor nucleus of the vagus. The A6 (locus coeruleus, LC) region is the largest NA cell area. The A7 area is localized in the pontine reticular formation and the A5 region lies rostrally to the Al group"2'. Three major ascending pathways emerge from the NA cell groups. The ventral noradrenergic bundle (ventral tegmental tract) arises from the Al, A2, A5 and A7 cell groups and from the LC and innervates predominantly the preoptic area, the hypothalamus and the limbic system. The dorsal noradrenergic bundle (dorsal tegmental tract) originates in the LC and projects to the frontal cortex and several hypothalamic nuclei. The dorsal periventricular tract originates in the A2 cell group and also collects fibres from the LC" 213 '. The noradrenergic input to the spinal cord arises mostly from the A5, A6 (LC) and A7 cell groups. The
majority of fibres innervating the intermediolateral column originate in the A5 cell group'6' (Fig. 1). Neuroanatomical, pharmacological and neurophysiological data provide the main evidence that the catecholaminergic system plays an important role in central cardiovascular regulation. The location of the A2 cell group coincides with the NTS, a site where the afferent fibres of the baroreceptor reflex terminate. The RVLM coincides with the localization of the Cl adrenergic cells, whereas Al noradrenergic cells are localized within the CVLM'101". The adrenergic neurons in the RVLM may mediate vasodepressor responses after activation of arterial baroreceptors121. These neurons are under the inhibitory influence of the CVLM, and this inhibition appears to be mediated by noradrenergic projections deriving from Al noradrenergic neurons'314'. Catecholaminergic neurons in the medulla and pons are also involved in transmission of primary visceral afferent information to the peptidergic neurons in the PVN and SON. The noradrenergic input to the PVN and SON arises from the A l , A2 and LC. The magnocellular neurons in the PVN are almost entirely innervated from the Al region'6'. The effects of pharmacological manipulation of the noradrenergic system in the brain or adrenoreceptors on BP and HR have been reviewed elsewhere'15'. In the present paper only the central actions of clonidine will be briefly dealt with in this respect.
CENTRAL HYPOTENSIVE ACTION OF CLONIDINE
Clonidine (CLO) is a classical avadrenoreceptor agonist and a potent centrally acting antihypertensive drug. Although the site(s) and mechanisms of the hypotensive action of CLO in the brain remain unclear, this drug certainly reduces the sympathetic output from the brain to peripheral organs such as the heart and the vasculature'16'. It has been further suggested that cr2-adrenoreceptors in the dorsal vagal
Hippocampus Cortex
Medulla oblongata
Olfactory bulb Hypothalamus
Figure 1 Schematic illustration representing the location of the catecholaminergic cell bodies (A groups) and pathways in a sagittal section of the rat brain. 1. ventral NA bundle 2. dorsal NA bundle 3. dorsal periventricular tract. 4. bulbospinal catecholaminergic pathway. CC, corpus callosum; CP, caudate-putamen; GP, globus pallidus.
12 J. Oilman and T. Unger
complex mediate the effects of CLO on the activity of vagal preganglionic neurons. The high density of the specific CLO binding sites in this area would support such an assumption'17'. A high density of CLO binding sites has also been demonstrated in the A5 noradrenergic cell group, the region that may transmit the visceroceptive output from the ventrolateral medulla to the spinal cord'6'. It has further been reported that part of the hypotensive effects of CLO injected into the NTS is brought about by inhibition of vasopressin release into the circulation'18'. According to recent findings, the central hypotensive action of CLO might involve an action on non-adrenergic, 'imidazoline preferring' receptor sites"9'. SEROTONIN
Using fluorescence microscopy, nine distinct nuclei (B1-B9) containing serotonin (5-HT) have been described in the brain. Most of the serotonergic perikarya coincide with the raphe nuclei. The dorsal raphe nucleus (DRN) (B7), the largest among the raphe nuclei, its caudal pontine extension (B6) and the median raphe nucleus (B8) are located in the mesencephalon. The ascending 5-HT fibres originate from these nuclei"2-20'. The nucleus raphe magnus (NRM) (B3), second in size among the raphe nuclei, is located in the medial medulla, rostrally to the inferior olivae. The nucleus raphe pallidus (Bl) and nucleus raphe obscurus (B2) lie caudally to the B3 at the level of inferior olivae. The latter are small nuclei containing only a few 5-HT cells'12-20'. There are two major ascending 5-HT systems innervating the forebrain structures and cerebellum. The transtegmental 5-HT system is formed by fibres deriving from the DRN and B6 and, to a lesser extent, from the median raphe nucleus (B8). The periventricular 5-HT system originates from the rostral part of
the DRN'12-21'. The hypothalamus is densely innervated with 5-HT terminals. In the PVN, the majority of the 5-HT terminals are concentrated in the parvocellular part of the nucleus. In the magnocellular part of the PVN, 5-HT fibres innervate predominantly oxytocinergic neurons. These 5-HT projections arise from DRN, B8 and B9 cell groups'22'. The descending bulbospinal 5-HT pathway originates in B1-B3 medullary raphe nuclei and provides a dense serotonergic innervation of the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord'12-23'. Of the rostrally located 5-HT perikarya, one third of the 5-HT neurons in the reticular formation (B9) project to the spinal cord, a few spinal projections also originate from the DRN'23' (Fig. 2). 5-HT fibres innervating the sympathetic preganglionic neurons also contain substance P124'. In recent years, great progress has been made concerning the pharmacology of 5-HT receptors. According to the current classification, three classes of 5-HT receptors, 5-HT,, 5-HT2 and 5-HT3 can be distinguished. The group of 5-HT, receptors consists of four receptor subtypes 1A, IB, 1C and ID' 25 '. Because of the multiplicity of 5-HT receptors and their uneven distribution in the brain it is not surprising that conflicting results and conclusions have been presented concerning the role of the brain's 5-HT system in cardiovascular control. The cardiovascular effects of altering 5-HT levels in the brain and the effects of administration of various 5-HT agonists and antagonists have been reviewed elsewhere"5-20'. Therefore, in the present article, only the role of the bulbospinal serotonergic system in controlling the activity of sympathetic preganglionic neurons and the central hypotensive action of 5-HT,A agonists will be dealt with. The majority of the 5-HT fibres innervating the sympathetic preganglionic neurons derive from the B1-B3 raphe nuclei'23'. Measurement of the changes in
Hippocampus Cortex
Medulla oblongata
Olfactory bulb Hypothalamus
Figure 2 Schematic illustration representing the location of the serotoninergic cell bodies (B groups) and pathways in sagittal section of the rat brain. Bl n.raphe obscurus, B2 n.raphe pallidus, B3 n.raphe magnus, B7 dorsal raphe nucleus, B8 median raphe nucleus. 1. transtegmental 5-HT system, 2. periventricular 5-HT system, 3. bulbospinal 5-HT pathway. For other abbreviations see Fig. 1.
Central mechanisms regulating blood pressure 13
BP, HR and sympathetic nerve activity in response to electrical stimulation of various sites within the medullary raphe neurons have demonstrated that these nuclei are not homogeneous in function with respect to cardiovascular control. These studies have also suggested the existence of diverse 5-HT pathways mediating the 5-HT action on sympathetic preganglionic neurons'25"27'. The sympathetic preganglionic neurons responded to locally applied 5-HT by excitation; however, inhibition or bipolar responses were also recorded, suggesting that different 5-HT receptor subtypes in the spinal cord may be involved in 5-HT action'28'. Pharmacological studies have provided evidence that the inhibitory effect of 5-HT on sympathetic activity is mediated by 5-HT2 receptors. On the other hand, 5-HT,-like receptors may mediate the excitatory action of 5-HT in the spinal cord'28-29'. CENTRAL HYPOTENSIVE EFFECTS OF 5-HT, A AGONISTS
Substantial evidence has been accumulated that suggests that central 5-HTIA receptors may play a role in the regulation of vascular tone. The 5-HT,A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8OH-DPAT) was shown to lower BP and HR through central mechanisms independently of the baroreceptor reflex130'. The cardiovascular response to 8-OH-DPAT was inhibited by the nonselective 5-HT antagonists, metergoline and methiothepine, and by the selective 5-HT,A receptor antagonist, 8-methoxy-2-(N-2chloroethyl-N-n propyl) amino tetralin (8-MeOC1EPAT)'3". Urapidil, another 5-HT,A agonist, binds with high affinity to 5-HT1A receptors, while also binding to ar,-adrenoreceptors. Both inhibition of peripheral ar,-adrenoreceptors and activation of central 5-HT1A receptors contribute to the hypotensive action of urapidil'32-331. The central actions of 5-HTIA agonists probably result from activation of somatodendritic 5-HT autoreceptors of the 5-HT1A subtype in the raphe nuclei with a consequent decrease in firing of the 5-HT neurons'25'. Decreased firing of the medullary raphe nuclei reduces the excitatory input to the sympathetic preganglionic neurons in the spinal cord'331. Experimental data suggest that at least some of the hypotensive effects of 5-HT,A receptor agonists result from stimulation of the 5-HT,A receptors located in the intermediate area of the ventral medulla'34', and that the hypotensive and bradycardic effects of 5-HT1A agonists can be differentiated from those of classical avadrenoreceptors'16'. Unlike clonidine, 5-HTIA agonists increase the central vagal drive to the heart probably via activation of the 5-HT,A receptors in the cardiac vagal motor neurons'351. Neuropeptides involved in central cardiovascular control VASOPRESSIN
Arginine-vasopressin (AVP) is synthesized in the
PVN and in the SON; the suprachiasmatic nucleus (SCN) is another source of AVP in the hypothalamus13*1. AVP from the magnocellular part of the PVN and from the SON is transported to the posterior pituitary and released in response to appropriate stimuli. In addition to vasopressinergic projections to the posterior pituitary and to the median eminence, AVP, perikarya in the PVN send fibers to many brainstem and spinal cord sites. These are known to be involved in central cardiovascular control, such as the NTS, the dorsal vagal complex, the LC and the intermediolateral column of the spinal cord'5-37'. The PVN and the SON receive, among others, direct neuronal input from the catecholaminergic cell groups A l , A2 and from the LC. Adrenergic fibers arising from the Cl and C2 cell groups also appear to contribute to the catecholaminergic innervation of the PVN and the SON161. Moreover, the PVN and the SON receive direct input from the subfornical organ (SFO) and organum vasculosum laminae terminalis (OVLT)'38-39'. The neuronal connections between the circumventricular structures and vasopressinergic neurons in the PVN and SON play an important role in mediating the central effects of blood-borne and possibly also brain angiotensin II'40"42'. The neuronal connections of the vasopressinergic cell bodies suggest a role for central AVP in central cardiovascular regulation. Stimulation of central periventricular Vl-AVP receptors produces a characteristic haemodynamic response with an increase in blood pressure and marked sympathetic nerve activation'43-441. Microinjection of AVP into the LC or NTS also results in activation of the sympathetic nervous system and in an increase in BP and HR'45461. AVP stimulates the activity of vasomotor neurons in the RVLM by a mechanism involving Vl-AVP receptors'471. AVP acting on Vl-AVP receptors in the brain desensitizes the baroreceptor reflex, while circulatory AVP sensitizes it by acting on V2-AVP receptors accessible from the blood'44'. These data provide evidence which suggests there is direct interaction between AVP as a hormone and AVP as a neuropeptide in cardiovascular control mechanisms. ANGIOTENSIN II
Circulatory angiotensin II (ANG II) is recognized for its vasoconstrictor effects and for its role in the regulation of body fluids. In addition to these peripheral effects, circulating ANG II can promote an increase in BP, drinking behaviour and release of pituitary hormones through a direct action on specific ANG II receptors in the circumventricular organs which lack the blood brain barrier. In recent years, evidence has also accumulated that angiotensin peptides are synthesized in the CNS, and it is now well established that all components of the renin-angiotensin system (RAS) are present in the brain. Brain RAS appears to be regulated independently of peripheral RAS, and a number of studies
14 J. Culman and T. Unger
have demonstrated that brain RAS is involved in central blood pressure regulation; an overactive brain RAS may be one of the factors involved in the pathogenesis of hypertension'421. ANG II-immunoreactive cells are located, among many other brain regions, in the PVN, SON and in the SCN of the hypothalamus. In the PVN, ANG II-immunoreactive cells were found in all portions with the greatest concentration of cells in the magnocellular part of the nucleus. A high density of ANG II nerve terminals has been found in the median eminence, PVN, SON and SFO. ANG IIimmunoreactive cells are also located in the SFO'42'. The distribution of specific receptors for ANG II correlates well with the localization of immunoreactive ANG II. High binding of ANG II was found in the septum, thalamus, hypothalamus and in the medulla oblongata. A very high density of rat brain ANG II receptors is present in the SFO, PVN, NTS, OVLT and in the area postrema142'48'4"1. ANG II receptors in areas involved in central cardiovascular control, such as the SFO, PVN, NTS and area postrema, appear to be of the ANG II-AT, subtype. ANG II receptors in the inferior olivae or in the superior collide belong to the ANG II-AT2 subtype150-511. Central ANG II and AVP systems are closely related, and microinjection of ANG II into the PVN was reported to produce a dose-dependent increase in plasma AVP1521. The circumventricular organs play an important role in the interaction between either circulatory or central ANG II on the one side and vasopressinergic neurons on the other. For instance, it has been demonstrated that the increased excitability of the vasopressinergic and oxytocinergic neurons in the PVN and SON in response to systemic ANG II is mediated via the SFO'53'. Recent neuroanatomical and electrophysiological studies revealed that at least part of the neuronal output from the SFO to the SON arises from the ANG II-immunoreactive cells in the SFO. ANG II itself may probably mediate the excitatory input from the SFO to the SON"4'. Stimulation of central ANG II receptors results in a pressor response, release of AVP and other hormones from the pituitary and induction of drinking behaviour1421. The pressor effects of ANG II administered intracerebroventricularly (icv) is mediated by both the sympathetic nervous system and release of AVP, since combined pretreatment with intravenous V,-AVP receptor angatonist and o-,adrenoreceptor antagonist is required to prevent the response completely1351. The pressor response to icv ANG II injections is initiated by AVP release, while HR and peripheral sympathetic activity are initially decreased. If the rats are allowed to drink, an increase in the sympathetic neuronal activity contributes to the pressor response1"1. The central effects of ANG II may require the participation of other neurotransmitter systems. For instance, ANG II-induced release of AVP from the pituitary gland appears to be mediated through an
ar-adrenergic stimulation in the PVN and SON"6-371. Pressor doses of ANG H-injected icv were shown to stimulate NE utilization in brainstem regions LC, n. raphe magnus and A l , and in the hypothalamus1581. Stimulation of central GABA-ergic receptors, on the other hand, attenuated the pressor response to centrally administered ANG II'591. ANG II may further serve as a modulator of the baroreceptor HR reflex. Experimental data indicate that the NTS may be a target organ for the action of ANG II of either central or peripheral origin'601. SUBSTANCE P
Substance P (SP) is a member of a family of peptides known as tachykinins. Two other tachykinins, neurokinin A and neurokinin B and novel neurokinin A-derived peptides are also present in mammalian brain. SP is widely distributed throughout the CNS. SP containing perikarya were demonstrated in the central gray, NRM, striatum, globus pallidus, and in the nucleus of the spinal trigeminal tract1121. High densities of SP-immunoreactive terminals and fibres have been found in the hypothalamus, medial preoptic area, substantia nigra, ventral tegmental area, NTS and nucleus dorsalis nervi vagi1"'621. The distribution of SP-nerve terminals in the latter two areas correlates with the high density of SP receptors in these regions'631. SP-containing fibres innervating the spinal cord mostly originate in the NRM. In the fibres terminating in the sympathetic preganglionic neurons, SP is colocalized with 5-HT1241. Experimental evidence suggests that SP may serve as a neurotransmitter at the first synapse of the baroreceptor reflex'*41. Injections of SP into the NTS produce hypotension and bradycardia'651. SP may exert excitatory effects on spinal sympathetic preganglionic neurons. SP-like neurons in the ventral medulla projecting to the intermediolateral column have been implicated in maintaining vasomotor tone'66'. Stimulation of the periventricular SP receptors in the brain induces a distinct haemodynamic response featuring a rise in BP, HR, sympathoadrenal activation, an increase in cardiac output, splanchnic and renal nerve activity, a decrease in the mesenteric and renal blood flow and an increase in hindlimb blood flow'67'6'1. This response pattern resembles the classical defence reaction. Recent findings suggest that hypothalamic SP receptors play an important role in mediating the SP-induced defence reaction'69'. The role of other classical neurotransmitters and neuropeptides in central cardiovascular control have recently been reviewed by others115'70'7". CONCLUSION
More recently, scientific interest has focused on the interaction between peptides and classical neurotransmitters in the central cardiovascular control. The co-existence of a number of peptides and monoamines in the same neuron provides a basis for such an
Central mechanisms regulating blood pressure 15
SFOj
OVLTSON
ANG II pathway Cateeholaminergic pathway AVP pathway Putative functional' ANG II pathway Figure 3 Schematic illustration showing the ANG II pathways, noradrenergic input to the PVN and SON and AVP input to the posterior pituitary. Activation of the ANG II receptors in the SFO and OVLT facilitates the release of NA in the PVN which results in increased secretion of AVP from the posterior pituitary. OVLT, organum vasculosum laminae terminalis; SFO, subfornical organ; PVN, paraventricular nucleus; SON, supraoptic nucleus; 3V, 3rd ventricle; PP, posterior pituitary; Al, A2 and A6, NA cell bodies.
interaction. The interaction between peptides and monoamines, and presynaptic or postsynaptic interactions between neuropeptides may modulate peptidergic effects and thus influence central cardiovascular control. For example, recent findings have suggested that at least part of the cardiovascular effects of ANG II in the NTS may involve an interaction with SP*72'. The pressor effect of central or circulatory ANG II requires an interaction of several neurotransmitter systems. Stimulation of ANG II receptors in circumventricular organs activates neuronal pathways to the PVN and SON, which results in increased release of NA from noradrenergic nerve terminals localized on AVP neurons. NA acting on aadrenoreceptors, in turn, stimulates the release of AVP into the circulation'56J7-73) (Fig. 3). It has been shown that peptides, ANG II and atrial natriuretic peptide (ANP) are localized in close proximity in brain areas involved in central cardiovascular electrolyte and volume control. Both peptides appear to be functionally antagonistic to each other with respect to release of pituitary hormones and natriuresis, drinking and sodium retention'741. Further investigations into the effects of classical neurotransmitters and neuropeptides on the functional activity of central cardiovascular centres may significantly contribute to our understanding of the central mechanisms responsible for the development and maintenance of hypertension. References [1] Qriello J, Caverson MM, Polosa C. Function of the ventrolateral medulla in the control of the circulation.
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analysis. J Cardiovasc Pharmacol 1987; 9: 328-47. [32] GroB G, Hanft G, Kolassa N. Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT 1A subtype and for ar,-adrenoreceptor binding sites. NaunynSchmiederberg's Arch Pharmacol 1987; 336: 597-601. [33] Kolassa N, Beller KD, Sanders KH. Evidence for the interaction of urapidil with 5-HT1A receptors in the brain leading to a decrease in blood pressure. Am J Cardiol 1989; 63: 36C-39C. [34] Mandal AK, KeUar KJ, Friedman E, Pineo SV, Hamosh P, Gillis RA. Importance of central nervous system serotonin-l A receptors for mediating the hypotensive effect of urapidil. J Pharmacol Exp Ther 1989; 251: 563-70. [35] Ramage AG. Influence of 5-HT )A receptor agonists on sympathetic and parasympathetic nerve activity. J Cardiovasc Pharmacol 1990; 15 (Suppl 7): S75-S85. [36] Vandersande F, Dierickx K, De Mey J. Identification of the vasopressin-neurophysin producing neurons of the rat suprachiasmatic nuclei. Cell Tiss Res 1975; 156: 377-80. [37] Nilaver G, Zimmerman EA, Wilkins J, Michaels J, Hoffman D, Silverman AJ. Magnocellular hypothalamic projections to the lower brain stem and spinal cord. Neuroendocrinology 1980; 30: 150-8. [38] Miselis RR, Shapiro RE, Hand PJ. Subfornical organ efferents to neural system for control of body water. Science 1979; 205: 1022-4. [39] Gutman MB, Ciriello J, Mogenson GJ. Electrophysiological identification of forebrain connections of the subfornical organ. Brain Res 1986; 382: 119-28. [40] Gutman MB, Ciriello J, Mogenson GJ. Effects of plasma angiotensin II and hyperaatremia on subfornical organ neurons. Am J Physiol 1988; 23: R746-54. [41] Thrasher TN, Keil LC. Regulation of drinking and vasopressin secretion: role of organum vasculosum laminae terminals. Am J Physiol 1987; 22: R108-R120. [42] Unger T, Badoer E, Ganten D, Lang RE, Rettig R. Brain angiotensin: pathways and pharmacology. Circulation 1988; 77 (Suppl 1): 1-40. [43] Unger T, Rohmeiss P, Becker H, Ganten D, Lang RE, Petty M. Sympathetic activation following central vasopressin receptor stimulation in conscious rats. J Hypertens 1984; 2 (Suppl 3): 25-7. [44] Unger T, Rohmeiss P, Demmert G, Luft FC, Ganten D, Lang RE. Differential actions of neuronal and hormonal vasopressin on blood pressure and baroreceptor sensitivity in rats. J Cardiovasc Pharmacol 1986; 8 (Suppl 7): S81-S86. [45] Berecek K, Olpe HR, Jones RSG, Hofbauer KG. Microinjection of vasopressin into the locus coeruleus of conscious rats. Am J Physiol 1984; 16: H675-H681. [46] Matsuguchi H, Sharabi FM, Gordon FJ, Johnson AK, Schmid PG. Blood pressure and heart rate responses to microinjections of vasopressin into the nucleus tractus solitarius region of rat. Neuropharmacology 1982; 21: 687-93. [47] Andreatta-Van Leyen S, Averill DB, Ferrario CM. Cardiovascular actions of vasopressin at the ventrolateral medulla. Hypertension 1990; 15 (Suppl I): I-102-I-106. 48] Gehlert DR, Speth RC, Wamsley JK. Distribution of (l23I)angiotensin II binding sites in the rat brain: a quantitative autoradiographic study. Neuroscience 1986; 18: 837-56. [49] Mendelsohn FOA, Quirion R, Saavedra JM, Aguilera G, Catt KJ. Autoradiographic localization of angiotensin II receptors in rat brain. Proc Natl Acad Sci 1984; 81: 1575-9. [50] Tsutsumi K, Saavedra JM. Quantitative autoradiography reveals different angiotensin II receptor subtypes in selected rat brain nuclei. J Neurochem 1991; 56: 348-51. [51] Obermdller N, Unger T, Culman J, Gohlke P, de Gasparo M, Bottari SP. Distribution of angiotensin II receptor subtypes in rat brain nuclei. Neurosci Lett 1991; 132: 11-15. [52] Shoji M, Share L, Crofton JT. Effect on vasopressin release
Central mechanisms regulating blood pressure 17
of microinjection of angiotensin II into the paraventricular nucleus of conscious rats. Neuroendocrinology 1989; 50: 327-33. [53] Ferguson AV, Renaud LP. Systemic angiotensin acts at subfornical organ to facilitate activity of neurohypophyseal hormones. Am J Physiol 1986; 20: R712-R717. [54] Jhamandas JH, Lind RW, Renaud LP. Angiotensin II may mediate excitatory neurotransmission from the subfornical organ to the hypothalamic supraoptic nucleus: an anatomical and electrophysiological study in the rat. Brain Res 1989; 487: 52-61. [55] Unger T, Becker H, Petty M, et al. Differential effects of central angiotensin II and substance P on sympathetic nerve activity in conscious rats. Circ Res 1985; 56: 563-75. [56] Veltmar A, Qadri F, Culman J, Rascher W, Unger T. Catecholaminergic pathway involved in angiotensin IIinduced vasopressin release. J Hypertens 1991; 9 (Suppl 6): S56-7. [57] Stadler T, Veltmar A, Qadri F, Unger T. Angiotensin II evokes noradrenaline release from the paraventricular nucleus in conscious rats. Brain Res, 1992; 569: 117-22. [58] Summers C, Phillips MI. Central injection of angiotensin II alters catecholamine activity in rat brain. Am J Physiol 1983; 244: R257-R263. [59] Unger T, Bles F, Ganten D, Lang RE, Rettig R, Schwab NA. Gabaergic stimulation inhibits central actions of angiotensin II: pressor responses, drinking and release of vasopressin. Eur J Pharmacol 1983; 90: 1-9. [60] Michelini LC, Bonagamba LGH. Angiotensin II as a modulator of baroreceptor reflexes in the brainstem of conscious rats. Hypertension 1990, 15 (Suppl I): I-45-I-50. [61] Ljungdahl A, HOkfelt T, Nilsson G. Distribution of substance P-like immunoreactivity in the central nervous system of the rat. I. Cell bodies and nerve terminals. Neuroscience 1978; 3: 861-943. [62] Kawano H, Chiba T. Distribution of substance P immunoreactivity nerve terminals within the nucleus tractus solitarii of the rat Neurosci Lett 1984; 45: 175-9. [63] Helke CJ, Shults CW, Chase TN, O'Donohue TL.
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Autoradiographic localization of substance P receptors in rat medulla; effects of vagotomy and nodose ganglionectomy. Neuroscience 1984; 12: 215-23. Haeusler G, Osterwalder R. Evidence suggesting a transmitter or neuromodulatory role for substance P at the first synapse of the baroreceptor reflex. NaunynSchmiedeberg's Arch Pharmacol 1980, 314: 11-21. Kubo T, Kihara M. Blood pressure modulation by substance P in the rat nucleus tractus solitarius. Brain Res 1987; 413: 379-83. Loewy AD, Sawyer WB. Substance P antagonist inhibits vasomotor responses elicited from ventral medulla in rat. Brain Res 1982; 245: 379-83. Unger T, Becker H, Petty M et al. Differential effects of central angiotensin II and substance P on sympathetic nerve activity in conscious rats. Circ Res 1985; 56: 563-75. Unger T, Carolus S, Demmert G et al. Substance P induces a cardiovascular reaction in the rat: pharmacological characterization. Circ Res 1988; 63: 812-20. Itoi K, Jost N, Badoer E, TschSpe C, Culman J, Unger T. Localization of the substance P-induced cardiovascular responses in the rat hypothalamus. Brain Res 1991; 558: 123-6. Reid JL, Rubin PC. Peptides and central neural regulation of the circulation. Physiol Rev 1987, 67: 725-49. Gardiner S, Bennet T. Brain neuropeptides: actions on central cardiovascular control mechanisms. Brain Res Rev 1989, 14: 79-116. Barnes KL, Diz DI, Ferrario CM. Functional interactions between angiotensin II and substance P in the dorsal medulla. Hypertension 1991, 17: 1121-6. Leibowitz SH, Eidelman D, Suh JS, Diaz S, Sladek CD. Mapping study of noradrenergic stimulation of vasopressin release. Exp Neurol 1990; 110: 298-305. Unger T, Badoer Gareis C et al. Atrial natruiretic pcptide (ANP) as a neuropeptide: interaction with angiotensin II on volume and renal sodium handling. Br J din Pharmac 1990; 30: 83S-8S.
Central mechanisms regulating blood pressure: Circuits and transmitters J. CULMAN AND T. UNGER
Department of Pharmacology and German Institute for High Blood Pressure Research, University of Heidelberg, Germany
Introduction Adaptation of the cardiovascular system to an organism's requirements is achieved by interaction between central and peripheral regulatory mechanisms. Cardiovascular homeostasis is centrally controlled by a complex network of mechanisms involving several brain regions and neurotransmitter systems. The precise role of individual structures and agents in the central nervous system (CNS) controlling arterial blood pressure has not yet been established. Several brain regions, including the cerebral cortex and the hypothalamus, are involved in the generation of the final output to the vegetative nervous system; however, only a limited number of distinct brain nuclei play a direct role in central cardiovascular regulation. Neuroanatomical studies have revealed a dense network of interconnections between these nuclei. In the following, the organization of the central nervous system and the role of some neurotransmitter and neuropeptide systems, with regard to the regulation of blood pressure (BP) and heart rate (HR), are briefly reviewed.
NUCLEUS TRACTUS SOLITARII (NTS)
The NTS receives afferent inputs from arterial baroreceptors and chemoreceptors via the IXth and Xth cranial nerves. Central afferents derive from other regions in the medulla oblongata, the paraventricular nucleus (PVN) of the hypothalamus and amygdala1'•5|, and it is well established that NTS plays a key role in the central activation of the baroreceptor reflex. HYPOTHALAMIC NUCLEI
The paraventricular (PVN) and supraoptic nuclei (SON) represent an important site for the integration and regulation of neuroendocrine and autonomic processes'5'. The PVN receives afferent input, among others, from the ventrolateral medulla and locus coeruleus (LC), and neurons in the PVN project to the spinal cord, the parabrachial nucleus, the LC and to the dorsal vagal complex'3'6'. Electrical stimulation of these and other hypothalamic structures produce a wide range of cardiovascular effects. For instance, electrical stimulation of the posterior hypothalamus leads to a pressor response accompanied by an increase in locomotor activity17'. LIMBIC SYSTEM AND CORTEX
Brain areas involved in cardiovascular control AREAS IN THE MEDULLA OBLONGATA
Experimental evidence shows that neurotransmitter systems in the rostral part of the ventrolateral medulla (RVLM) provide a tonic excitatory drive to sympathetic preganglionic neurons'1'. Anatomical and neurophysiological studies revealed direct connections between the RVLM with a number of other brain areas which are involved in central control of the cardiovascular system. The RVLM receives direct neuronal input from the nucleus tractus solitarii (NTS), a site where the afferent neurons from the carotic sinus and aortic arch terminate'1'. The sympathoexcitatory neurons in the RVLM are under the inhibitory influence of NTS neurons'2'. The caudal parts of the ventrolateral medulla (CVLM) are also involved in central cardiovascular control. Stimulation of the CLVM produces a decrease in blood pressure (BP) and heart rate (HR)'31, and the RVLM seems to mediate the vasodepressor response elicited by stimulation of the CVLM' 34 '. 0195-668X/92/0A0010 + 08 $03.00/0
Lower brainstem cardiovascular centres are under the direct influence of the limbic system and cerebral cortex. The central amygdaloid nucleus may represent a link between the sensory cortical areas and the cardiovascular centres of the hypothalamus and brainstem. The central amygdala appears to play a role in the development of hypertension in spontaneously hypertensive rats'8'. Like the limbic system, the cerebral cortex is involved in transforming sensory inputs and emotions into cardiovascular reactions. DEFENCE REACTION
Electrical stimulation of certain hypothalamic or brainstem areas induces a typical integrated cardiovascular and behavioral reaction called a defence reaction. This reaction is characterized by an increase in BP and heart rate (HR), by vasoconstriction in the splanchnic, renal and cutaneous circulation and skeletal muscle vasodilation. The whole defence reaction pattern, which appears to be important in the cardiovascular response to stress, can be elicited after stimulation of certain areas in the hypothalamus or periaqueductal grey matter1''1. 1992 The European Society of Cardiology
Central mechanisms regulating blood pressure 11
Neurotransmitters involved in central cardiovascular control A number of classical neurotransmitters have been implicated in central cardiovascular control, among these, catecholamines and serotonin are particularly prominent. Other neurotransmitters include histamine, acetylcholine, y-aminobutyric acid (GABA) and a number of neuropeptides such as vasopressin, substance P, angiotensin II, opioid peptides, atrial natriuretic peptide (ANP) etc. These latter substances may act as classical neurotransmitters or as neuromodulators mediating the pre- and postsynaptic action of other neurotransmitters. MONOAMINES
Catecholamines Noradrenaline (NA) and adrenaline (A) cell bodies have been demonstrated in the lower brainstem. NA cell bodies are present in A1-A7 cell groups and A cell bodies in Cl and C2 cell groups'10"12'. The Al and Cl cell groups lie in the ventrolateral part of the medulla, A2 and C2 cover NTS territory and the dorsal motor nucleus of the vagus. The A6 (locus coeruleus, LC) region is the largest NA cell area. The A7 area is localized in the pontine reticular formation and the A5 region lies rostrally to the Al group"2'. Three major ascending pathways emerge from the NA cell groups. The ventral noradrenergic bundle (ventral tegmental tract) arises from the Al, A2, A5 and A7 cell groups and from the LC and innervates predominantly the preoptic area, the hypothalamus and the limbic system. The dorsal noradrenergic bundle (dorsal tegmental tract) originates in the LC and projects to the frontal cortex and several hypothalamic nuclei. The dorsal periventricular tract originates in the A2 cell group and also collects fibres from the LC" 213 '. The noradrenergic input to the spinal cord arises mostly from the A5, A6 (LC) and A7 cell groups. The
majority of fibres innervating the intermediolateral column originate in the A5 cell group'6' (Fig. 1). Neuroanatomical, pharmacological and neurophysiological data provide the main evidence that the catecholaminergic system plays an important role in central cardiovascular regulation. The location of the A2 cell group coincides with the NTS, a site where the afferent fibres of the baroreceptor reflex terminate. The RVLM coincides with the localization of the Cl adrenergic cells, whereas Al noradrenergic cells are localized within the CVLM'101". The adrenergic neurons in the RVLM may mediate vasodepressor responses after activation of arterial baroreceptors121. These neurons are under the inhibitory influence of the CVLM, and this inhibition appears to be mediated by noradrenergic projections deriving from Al noradrenergic neurons'314'. Catecholaminergic neurons in the medulla and pons are also involved in transmission of primary visceral afferent information to the peptidergic neurons in the PVN and SON. The noradrenergic input to the PVN and SON arises from the A l , A2 and LC. The magnocellular neurons in the PVN are almost entirely innervated from the Al region'6'. The effects of pharmacological manipulation of the noradrenergic system in the brain or adrenoreceptors on BP and HR have been reviewed elsewhere'15'. In the present paper only the central actions of clonidine will be briefly dealt with in this respect.
CENTRAL HYPOTENSIVE ACTION OF CLONIDINE
Clonidine (CLO) is a classical avadrenoreceptor agonist and a potent centrally acting antihypertensive drug. Although the site(s) and mechanisms of the hypotensive action of CLO in the brain remain unclear, this drug certainly reduces the sympathetic output from the brain to peripheral organs such as the heart and the vasculature'16'. It has been further suggested that cr2-adrenoreceptors in the dorsal vagal
Hippocampus Cortex
Medulla oblongata
Olfactory bulb Hypothalamus
Figure 1 Schematic illustration representing the location of the catecholaminergic cell bodies (A groups) and pathways in a sagittal section of the rat brain. 1. ventral NA bundle 2. dorsal NA bundle 3. dorsal periventricular tract. 4. bulbospinal catecholaminergic pathway. CC, corpus callosum; CP, caudate-putamen; GP, globus pallidus.
12 J. Oilman and T. Unger
complex mediate the effects of CLO on the activity of vagal preganglionic neurons. The high density of the specific CLO binding sites in this area would support such an assumption'17'. A high density of CLO binding sites has also been demonstrated in the A5 noradrenergic cell group, the region that may transmit the visceroceptive output from the ventrolateral medulla to the spinal cord'6'. It has further been reported that part of the hypotensive effects of CLO injected into the NTS is brought about by inhibition of vasopressin release into the circulation'18'. According to recent findings, the central hypotensive action of CLO might involve an action on non-adrenergic, 'imidazoline preferring' receptor sites"9'. SEROTONIN
Using fluorescence microscopy, nine distinct nuclei (B1-B9) containing serotonin (5-HT) have been described in the brain. Most of the serotonergic perikarya coincide with the raphe nuclei. The dorsal raphe nucleus (DRN) (B7), the largest among the raphe nuclei, its caudal pontine extension (B6) and the median raphe nucleus (B8) are located in the mesencephalon. The ascending 5-HT fibres originate from these nuclei"2-20'. The nucleus raphe magnus (NRM) (B3), second in size among the raphe nuclei, is located in the medial medulla, rostrally to the inferior olivae. The nucleus raphe pallidus (Bl) and nucleus raphe obscurus (B2) lie caudally to the B3 at the level of inferior olivae. The latter are small nuclei containing only a few 5-HT cells'12-20'. There are two major ascending 5-HT systems innervating the forebrain structures and cerebellum. The transtegmental 5-HT system is formed by fibres deriving from the DRN and B6 and, to a lesser extent, from the median raphe nucleus (B8). The periventricular 5-HT system originates from the rostral part of
the DRN'12-21'. The hypothalamus is densely innervated with 5-HT terminals. In the PVN, the majority of the 5-HT terminals are concentrated in the parvocellular part of the nucleus. In the magnocellular part of the PVN, 5-HT fibres innervate predominantly oxytocinergic neurons. These 5-HT projections arise from DRN, B8 and B9 cell groups'22'. The descending bulbospinal 5-HT pathway originates in B1-B3 medullary raphe nuclei and provides a dense serotonergic innervation of the sympathetic preganglionic neurons in the intermediolateral column of the spinal cord'12-23'. Of the rostrally located 5-HT perikarya, one third of the 5-HT neurons in the reticular formation (B9) project to the spinal cord, a few spinal projections also originate from the DRN'23' (Fig. 2). 5-HT fibres innervating the sympathetic preganglionic neurons also contain substance P124'. In recent years, great progress has been made concerning the pharmacology of 5-HT receptors. According to the current classification, three classes of 5-HT receptors, 5-HT,, 5-HT2 and 5-HT3 can be distinguished. The group of 5-HT, receptors consists of four receptor subtypes 1A, IB, 1C and ID' 25 '. Because of the multiplicity of 5-HT receptors and their uneven distribution in the brain it is not surprising that conflicting results and conclusions have been presented concerning the role of the brain's 5-HT system in cardiovascular control. The cardiovascular effects of altering 5-HT levels in the brain and the effects of administration of various 5-HT agonists and antagonists have been reviewed elsewhere"5-20'. Therefore, in the present article, only the role of the bulbospinal serotonergic system in controlling the activity of sympathetic preganglionic neurons and the central hypotensive action of 5-HT,A agonists will be dealt with. The majority of the 5-HT fibres innervating the sympathetic preganglionic neurons derive from the B1-B3 raphe nuclei'23'. Measurement of the changes in
Hippocampus Cortex
Medulla oblongata
Olfactory bulb Hypothalamus
Figure 2 Schematic illustration representing the location of the serotoninergic cell bodies (B groups) and pathways in sagittal section of the rat brain. Bl n.raphe obscurus, B2 n.raphe pallidus, B3 n.raphe magnus, B7 dorsal raphe nucleus, B8 median raphe nucleus. 1. transtegmental 5-HT system, 2. periventricular 5-HT system, 3. bulbospinal 5-HT pathway. For other abbreviations see Fig. 1.
Central mechanisms regulating blood pressure 13
BP, HR and sympathetic nerve activity in response to electrical stimulation of various sites within the medullary raphe neurons have demonstrated that these nuclei are not homogeneous in function with respect to cardiovascular control. These studies have also suggested the existence of diverse 5-HT pathways mediating the 5-HT action on sympathetic preganglionic neurons'25"27'. The sympathetic preganglionic neurons responded to locally applied 5-HT by excitation; however, inhibition or bipolar responses were also recorded, suggesting that different 5-HT receptor subtypes in the spinal cord may be involved in 5-HT action'28'. Pharmacological studies have provided evidence that the inhibitory effect of 5-HT on sympathetic activity is mediated by 5-HT2 receptors. On the other hand, 5-HT,-like receptors may mediate the excitatory action of 5-HT in the spinal cord'28-29'. CENTRAL HYPOTENSIVE EFFECTS OF 5-HT, A AGONISTS
Substantial evidence has been accumulated that suggests that central 5-HTIA receptors may play a role in the regulation of vascular tone. The 5-HT,A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8OH-DPAT) was shown to lower BP and HR through central mechanisms independently of the baroreceptor reflex130'. The cardiovascular response to 8-OH-DPAT was inhibited by the nonselective 5-HT antagonists, metergoline and methiothepine, and by the selective 5-HT,A receptor antagonist, 8-methoxy-2-(N-2chloroethyl-N-n propyl) amino tetralin (8-MeOC1EPAT)'3". Urapidil, another 5-HT,A agonist, binds with high affinity to 5-HT1A receptors, while also binding to ar,-adrenoreceptors. Both inhibition of peripheral ar,-adrenoreceptors and activation of central 5-HT1A receptors contribute to the hypotensive action of urapidil'32-331. The central actions of 5-HTIA agonists probably result from activation of somatodendritic 5-HT autoreceptors of the 5-HT1A subtype in the raphe nuclei with a consequent decrease in firing of the 5-HT neurons'25'. Decreased firing of the medullary raphe nuclei reduces the excitatory input to the sympathetic preganglionic neurons in the spinal cord'331. Experimental data suggest that at least some of the hypotensive effects of 5-HT,A receptor agonists result from stimulation of the 5-HT,A receptors located in the intermediate area of the ventral medulla'34', and that the hypotensive and bradycardic effects of 5-HT1A agonists can be differentiated from those of classical avadrenoreceptors'16'. Unlike clonidine, 5-HTIA agonists increase the central vagal drive to the heart probably via activation of the 5-HT,A receptors in the cardiac vagal motor neurons'351. Neuropeptides involved in central cardiovascular control VASOPRESSIN
Arginine-vasopressin (AVP) is synthesized in the
PVN and in the SON; the suprachiasmatic nucleus (SCN) is another source of AVP in the hypothalamus13*1. AVP from the magnocellular part of the PVN and from the SON is transported to the posterior pituitary and released in response to appropriate stimuli. In addition to vasopressinergic projections to the posterior pituitary and to the median eminence, AVP, perikarya in the PVN send fibers to many brainstem and spinal cord sites. These are known to be involved in central cardiovascular control, such as the NTS, the dorsal vagal complex, the LC and the intermediolateral column of the spinal cord'5-37'. The PVN and the SON receive, among others, direct neuronal input from the catecholaminergic cell groups A l , A2 and from the LC. Adrenergic fibers arising from the Cl and C2 cell groups also appear to contribute to the catecholaminergic innervation of the PVN and the SON161. Moreover, the PVN and the SON receive direct input from the subfornical organ (SFO) and organum vasculosum laminae terminalis (OVLT)'38-39'. The neuronal connections between the circumventricular structures and vasopressinergic neurons in the PVN and SON play an important role in mediating the central effects of blood-borne and possibly also brain angiotensin II'40"42'. The neuronal connections of the vasopressinergic cell bodies suggest a role for central AVP in central cardiovascular regulation. Stimulation of central periventricular Vl-AVP receptors produces a characteristic haemodynamic response with an increase in blood pressure and marked sympathetic nerve activation'43-441. Microinjection of AVP into the LC or NTS also results in activation of the sympathetic nervous system and in an increase in BP and HR'45461. AVP stimulates the activity of vasomotor neurons in the RVLM by a mechanism involving Vl-AVP receptors'471. AVP acting on Vl-AVP receptors in the brain desensitizes the baroreceptor reflex, while circulatory AVP sensitizes it by acting on V2-AVP receptors accessible from the blood'44'. These data provide evidence which suggests there is direct interaction between AVP as a hormone and AVP as a neuropeptide in cardiovascular control mechanisms. ANGIOTENSIN II
Circulatory angiotensin II (ANG II) is recognized for its vasoconstrictor effects and for its role in the regulation of body fluids. In addition to these peripheral effects, circulating ANG II can promote an increase in BP, drinking behaviour and release of pituitary hormones through a direct action on specific ANG II receptors in the circumventricular organs which lack the blood brain barrier. In recent years, evidence has also accumulated that angiotensin peptides are synthesized in the CNS, and it is now well established that all components of the renin-angiotensin system (RAS) are present in the brain. Brain RAS appears to be regulated independently of peripheral RAS, and a number of studies
14 J. Culman and T. Unger
have demonstrated that brain RAS is involved in central blood pressure regulation; an overactive brain RAS may be one of the factors involved in the pathogenesis of hypertension'421. ANG II-immunoreactive cells are located, among many other brain regions, in the PVN, SON and in the SCN of the hypothalamus. In the PVN, ANG II-immunoreactive cells were found in all portions with the greatest concentration of cells in the magnocellular part of the nucleus. A high density of ANG II nerve terminals has been found in the median eminence, PVN, SON and SFO. ANG IIimmunoreactive cells are also located in the SFO'42'. The distribution of specific receptors for ANG II correlates well with the localization of immunoreactive ANG II. High binding of ANG II was found in the septum, thalamus, hypothalamus and in the medulla oblongata. A very high density of rat brain ANG II receptors is present in the SFO, PVN, NTS, OVLT and in the area postrema142'48'4"1. ANG II receptors in areas involved in central cardiovascular control, such as the SFO, PVN, NTS and area postrema, appear to be of the ANG II-AT, subtype. ANG II receptors in the inferior olivae or in the superior collide belong to the ANG II-AT2 subtype150-511. Central ANG II and AVP systems are closely related, and microinjection of ANG II into the PVN was reported to produce a dose-dependent increase in plasma AVP1521. The circumventricular organs play an important role in the interaction between either circulatory or central ANG II on the one side and vasopressinergic neurons on the other. For instance, it has been demonstrated that the increased excitability of the vasopressinergic and oxytocinergic neurons in the PVN and SON in response to systemic ANG II is mediated via the SFO'53'. Recent neuroanatomical and electrophysiological studies revealed that at least part of the neuronal output from the SFO to the SON arises from the ANG II-immunoreactive cells in the SFO. ANG II itself may probably mediate the excitatory input from the SFO to the SON"4'. Stimulation of central ANG II receptors results in a pressor response, release of AVP and other hormones from the pituitary and induction of drinking behaviour1421. The pressor effects of ANG II administered intracerebroventricularly (icv) is mediated by both the sympathetic nervous system and release of AVP, since combined pretreatment with intravenous V,-AVP receptor angatonist and o-,adrenoreceptor antagonist is required to prevent the response completely1351. The pressor response to icv ANG II injections is initiated by AVP release, while HR and peripheral sympathetic activity are initially decreased. If the rats are allowed to drink, an increase in the sympathetic neuronal activity contributes to the pressor response1"1. The central effects of ANG II may require the participation of other neurotransmitter systems. For instance, ANG II-induced release of AVP from the pituitary gland appears to be mediated through an
ar-adrenergic stimulation in the PVN and SON"6-371. Pressor doses of ANG H-injected icv were shown to stimulate NE utilization in brainstem regions LC, n. raphe magnus and A l , and in the hypothalamus1581. Stimulation of central GABA-ergic receptors, on the other hand, attenuated the pressor response to centrally administered ANG II'591. ANG II may further serve as a modulator of the baroreceptor HR reflex. Experimental data indicate that the NTS may be a target organ for the action of ANG II of either central or peripheral origin'601. SUBSTANCE P
Substance P (SP) is a member of a family of peptides known as tachykinins. Two other tachykinins, neurokinin A and neurokinin B and novel neurokinin A-derived peptides are also present in mammalian brain. SP is widely distributed throughout the CNS. SP containing perikarya were demonstrated in the central gray, NRM, striatum, globus pallidus, and in the nucleus of the spinal trigeminal tract1121. High densities of SP-immunoreactive terminals and fibres have been found in the hypothalamus, medial preoptic area, substantia nigra, ventral tegmental area, NTS and nucleus dorsalis nervi vagi1"'621. The distribution of SP-nerve terminals in the latter two areas correlates with the high density of SP receptors in these regions'631. SP-containing fibres innervating the spinal cord mostly originate in the NRM. In the fibres terminating in the sympathetic preganglionic neurons, SP is colocalized with 5-HT1241. Experimental evidence suggests that SP may serve as a neurotransmitter at the first synapse of the baroreceptor reflex'*41. Injections of SP into the NTS produce hypotension and bradycardia'651. SP may exert excitatory effects on spinal sympathetic preganglionic neurons. SP-like neurons in the ventral medulla projecting to the intermediolateral column have been implicated in maintaining vasomotor tone'66'. Stimulation of the periventricular SP receptors in the brain induces a distinct haemodynamic response featuring a rise in BP, HR, sympathoadrenal activation, an increase in cardiac output, splanchnic and renal nerve activity, a decrease in the mesenteric and renal blood flow and an increase in hindlimb blood flow'67'6'1. This response pattern resembles the classical defence reaction. Recent findings suggest that hypothalamic SP receptors play an important role in mediating the SP-induced defence reaction'69'. The role of other classical neurotransmitters and neuropeptides in central cardiovascular control have recently been reviewed by others115'70'7". CONCLUSION
More recently, scientific interest has focused on the interaction between peptides and classical neurotransmitters in the central cardiovascular control. The co-existence of a number of peptides and monoamines in the same neuron provides a basis for such an
Central mechanisms regulating blood pressure 15
SFOj
OVLTSON
ANG II pathway Cateeholaminergic pathway AVP pathway Putative functional' ANG II pathway Figure 3 Schematic illustration showing the ANG II pathways, noradrenergic input to the PVN and SON and AVP input to the posterior pituitary. Activation of the ANG II receptors in the SFO and OVLT facilitates the release of NA in the PVN which results in increased secretion of AVP from the posterior pituitary. OVLT, organum vasculosum laminae terminalis; SFO, subfornical organ; PVN, paraventricular nucleus; SON, supraoptic nucleus; 3V, 3rd ventricle; PP, posterior pituitary; Al, A2 and A6, NA cell bodies.
interaction. The interaction between peptides and monoamines, and presynaptic or postsynaptic interactions between neuropeptides may modulate peptidergic effects and thus influence central cardiovascular control. For example, recent findings have suggested that at least part of the cardiovascular effects of ANG II in the NTS may involve an interaction with SP*72'. The pressor effect of central or circulatory ANG II requires an interaction of several neurotransmitter systems. Stimulation of ANG II receptors in circumventricular organs activates neuronal pathways to the PVN and SON, which results in increased release of NA from noradrenergic nerve terminals localized on AVP neurons. NA acting on aadrenoreceptors, in turn, stimulates the release of AVP into the circulation'56J7-73) (Fig. 3). It has been shown that peptides, ANG II and atrial natriuretic peptide (ANP) are localized in close proximity in brain areas involved in central cardiovascular electrolyte and volume control. Both peptides appear to be functionally antagonistic to each other with respect to release of pituitary hormones and natriuresis, drinking and sodium retention'741. Further investigations into the effects of classical neurotransmitters and neuropeptides on the functional activity of central cardiovascular centres may significantly contribute to our understanding of the central mechanisms responsible for the development and maintenance of hypertension. References [1] Qriello J, Caverson MM, Polosa C. Function of the ventrolateral medulla in the control of the circulation.
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