Physiological actions of angiotensin II mediated by AT1 AND AT2 receptors in the brain

1. Autoradiographic binding studies have shown that the AT(1) receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT(1) receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord. 2. While there are differences between species, AT(2) receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat. 3. Circulating AngII acts on AT(1) receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking. 4. Centrally administered AngII may act on AT(1) receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion. 5. Recent evidence shows that centrally administered AT(1) antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses. 6. Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT(1) receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.     

ANTEROVENTRAL WALL OF THE THIRD VENTRICLE AND DORSAL LAMINA TERMINALIS: HEADQUARTERS FOR CONTROL OF BODY FLUID HOMEOSTASIS?

1. The subfornical organ, median preoptic nucleus and the organum vasculosum of the lamina terminalis (OVLT) are a series of structures situated in the anterior wall of the third ventricle and form the lamina terminalis. The OVLT and ventral part of the median preoptic nucleus are part of a region known as the anteroventral third ventricle region.
2. Data from many laboratories, using techniques ranging from lesions, electrophysiology, neuropharmacology, Fos expression, immunohistochemistry and receptor localization, indicate that the tissue in the lamina terminalis plays a major role in many aspects of body fluid and electrolyte balance.
3. The subfornical organ and OVLT lack the blood-brain barrier and detect alterations in plasma tonicity and the concentrations of circulating hormones such as angiotensin II and possibly atrial natriuretic peptide and relaxin.
4. This information is then integrated within the lamina terminalis (probably in the median preoptic nucleus) with neural signals from other brain regions. The neural output from the lamina terminalis is distributed to a number of effector sites including the paraventricular (both parvo- and magno-cellular parts) and supraoptic nuclei and influences vasopressin secretion, water drinking, salt intake, renin secretion, renal sodium excretion and cardiovascular regulation.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

INTEGRATIVE ROLE OF THE LAMINA TERMINALIS IN THE REGULATION OF CARDIOVASCULAR AND BODY FLUID HOMEOSTASIS

1. Cardiovascular and body fluid homeostasis depends upon the activation and co-ordination of reflexes and behavioural responses. In order to accomplish this, the brain receives and processes both neural and chemical input. Once in the brain, information from sources signalling the status of the cardiovascular system and body fluid balance travels, and is integrated, throughout a widely distributed neural network. Recent studies using neuroanatomical and functional techniques have identified several key areas within this neural network. One major processing node is comprised of structures located along the lamina terminalis. 2. Structures associated with the lamina terminalis include the median preoptic nucleus (MePO) and two sensory circumventricular organs (SCVO), the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). Current evidence indicates that blood-borne signals, such as angiotensin II (AngII), reach SCVO (e.g. SFO) where they are transduced. This information is then carried via neural pathways to brain nuclei (e.g. MePO) where it is integrated with other inputs, such as those derived from systemic arterial blood pressure and volume receptors. 3. Because of their receptive and integrative functions, lamina terminalis structures are essential for the normal control of hormone release (e.g. vasopressin), sympathetic activation and behaviours (thirst and salt appetite), which collectively contribute to maintenance of cardiovascular and body fluid homeostasis.     

Circumventricular Organs: Gateways to the Brain Multisynaptic Neuronal Pathways From The Submandibular And Sublingual Glands To The Lamina Terminalis In The Rat: A Model For The Role Of The Lamina Terminalis In The Control Of Osmo- And Thermoregulatory Behaviour

1. The putative regulatory role of the lamina terminalis in the central control of salivation was investigated in the rat using the viral‐tracing technique and Fos‐immunohistochemistry. 2. Neurons situated in the lamina terminalis, such as the vascular organ of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO), were retrogradely labelled after pseudorabies virus injections into the submandibular or sublingual gland. 3. Viral tracing combined with glandular denervation showed that lamina terminalis structures sent efferents, in particular, to the parasympathetic side of submandibular gland innervation. 4. Saliva lost under heat stress has severe implications for the body fluid economy of rats and a key to the understanding of the central regulation of heat‐induced salivation may be the integrative role of the lamina terminalis processing thermoregulatory and osmoregulatory information.     

Forebrain osmotic regulation of the sympathetic nervous system

1. Accumulating evidence in both humans and animals indicates that acute increases in plasma osmolality elevate sympathetic nerve activity (SNA). In addition, plasma hyperosmolality (or hypernatraemia) can produce sustained increases in SNA and arterial blood pressure (ABP) through stimulation of forebrain osmoreceptors. 2. Although an abundance of information exists regarding the osmoregulatory circuits for thirst and secretion of antidiuretic hormone, much less is known about those pathways and synaptic mechanisms linking osmotic perturbations and SNA. To date, the available evidence suggests that osmosensitive sites within the forebrain lamina terminalis, such as the organum vasculosum of the lamina terminalis, are key elements that link plasma hypertonicity to elevated SNA. 3. The major efferent target of osmosensitive regions in the forebrain lamina terminalis is the hypothalamic paraventricular nucleus (PVH). Evidence from a number of studies indicates that the PVH contributes to both acute and chronic osmotically driven increases in SNA. In turn, PVH neurons increase SNA through a direct vasopressinergic spinal pathway and/or a glutamatergic pathway to bulbospinal sympathetic neurons of the rostral ventrolateral medulla. 4. Future studies are needed to: (i) define the contribution of various osmosensitive regions of the forebrain lamina terminalis to acute and chronic osmotically driven increases in SNA; (ii) identify the cellular mechanisms and neural circuitry linking plasma osmolality and SNA; and (iii) define whether such mechanisms contribute to elevated SNA in salt-sensitive hypertension.     

ACTIONS OF ANGIOTENSIN IN THE SUBFORNICAL ORGAN AND AREA POSTREMA: IMPLICATIONS FOR LONG TERM CONTROL OF AUTONOMIC OUTPUT

1. Considerable physiological and anatomical evidence indicates that circulating angiotensin II (AngII), plays important roles in the long-term regulation of autonomic output as a result of actions in two circumventricular structures, the subfornical organ (SFO) and area postrema (AP). 2. Extracellular recordings have demonstrated excitatory actions of AngII on neurons from both of these structures which are ATi receptor mediated, maintained when cells are placed in synaptic isolation, and are dose dependent. Interestingly SFO neurons appear to be an order of magnitude more sensitive to AngII than those in AP. 3. Recent calcium imaging studies have demonstrated that AngII induces increases in intracellular calcium in both SFO and AP neurons. Whole cell patch recordings have also begun to provide important information suggesting that AngII actions may modulate voltage activated ion channels in these two structures to elicit its observed actions on circumventricular organs (CVO) neurons at the blood-brain interface. 4. Through these actions circulating AngII is thus able to influence efferent projections from these CVO which in turn influence the output of hypothalamic cells projecting to the posterior pituitary (vasopressin secretion), nucleus tractus soli-tarius (NTS), and intermediolateral cell column of the spinal cord (to influence sympathetic preganglionics), and medullary neurons in the NTS.     

Role of angiotensin II receptors in the regulation of vasomotor neurons in the ventrolateral medulla

1. There is a high density of angiotensin type 1 (AT1) receptors in various brain regions involved in cardiovascular regulation. The present review will focus on the role of AT1 receptors in regulating the activity of sympathetic premotor neurons in the rostral part of the ventrolateral medulla (VLM), which are known to play a pivotal role in the tonic and phasic regulation of sympathetic vasomotor activity and arterial pressure. 2. Microinjection of angiotensin (Ang) II into the rostral VLM (RVLM) results in an increase in arterial pressure and sympathetic vasomotor activity. These effects are blocked by prior application of losartan, a selective AT1 receptor antagonist, indicating that they are mediated by AT1 receptors. However, microinjection of AngII into the RVLM has no detectable effect on respiratory activity, indicating that AT1 receptors are selectively or even exclusively associated with vasomotor neurons in this region. 3. Under normal conditions in anaesthetized animals, AT1 receptors do not appear to contribute significantly to the generation of resting tonic activity in RVLM sympathoexcitatory neurons. However, recent studies suggest that they contribute significantly to the tonic activity of these neurons under certain conditions, such as salt deprivation or heart failure, or in spontaneously hypertensive or genetically modified rats in which the endogenous levels of AngII are increased or in which AT1 receptors are upregulated. 4. Recent evidence also indicates that AT1 receptors play an important role in mediating phasic excitatory inputs to RVLM sympathoexcitatory neurons in response to activation of some neurons within the hypothalamic paraventricular nucleus. The physiological conditions that lead to activation of these AT1 receptor-mediated inputs are unknown. Further studies are also required to determine the cellular mechanisms of action of AngII in the RVLM and its interactions with other neurotransmitters in that region.     

Role of AT1 receptors in the central control of sympathetic vasomotor function

1. In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits. 2. In conscious rabbits, fourth ventricular infusions of AngII produced dose-dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000-fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction. 3. The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms. 4. In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased. 5. The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT(1) antagonist losartan injected into the 4V. These results suggest that mainly AT(1) receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex. 6. Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes. 7. Our studies suggest that there are sympathoexcitatory AT(1) receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT(1) receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.     

Anteroventral third ventricle periventricular tissue contributes to cardiac baroreflex responses

1. The studies reviewed in the present paper demonstrate that the anteroventral third ventricle (AV3V) region contains tissue that can modify cardiac baroreflex sensitivity in response to circulating angiotensin (Ang)II and hyperosmolality. 2. The response to hyperosmolality appears to be mediated by noradrenergic receptors. Although the role of noradrenergic receptors in the AV3V region in modification of baroreflex-induced responses to AngII has not been directly tested, this neurotransmitter is a good candidate for control of heart rate because noradrenaline in the AV3V region is critical for mediating other responses to AngII. 3. Results from studies indicate that the AV3V region is part of a central nervous system circuit involved in modulation of cardiac baroreflex sensitivity by circulating substances, possibly acting at the organum vasculosum lamina terminalis. 4. The findings extend the role of the AV3V periventricular tissue as a central site integrating autonomic nervous system function by demonstrating that this brain area contributes to cardiac function, in addition to its well-characterized role in sympathetic nervous system regulation of blood pressure and mechanisms of fluid and electrolyte regulation.     

Circumventricular Organs: Gateways to the BrainLeptin Receptors In Hypothalamus And Circumventricular Organs

1. The adipose tissue‐derived hormone leptin reduces food intake and bodyweight via leptin receptors (Ob‐R) in the hypothalamus. 2. Leptin receptor immunoreactivity, demonstrated with an antiserum recognizing all Ob‐R isoforms, is present in hypothalamic neurons of the medial and lateral preoptic area, organum vasculosum lamina terminalis, subfornical organ, periventricular, suprachiasmatic, supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial, ventromedial hypothalamic and tuberomammillary nuclei and lateral hypothalamic area. In the brainstem, Ob‐R immunoreactivity is present in the area postrema, nucleus tractus solitarius, hypoglossal nucleus and dorsal motor nucleus of the vagus nerve. 3. Leptin receptor immunoreactivity is present in magnocellular vasopressin and oxytocin neurons of the SON and PVN, in parvocellular corticotropin‐releasing hormone neurons of the PVN, neuropeptide Y and pro‐opiomelanocortin neurons of the ARC and in melanin‐concentrating hormone neurons of the lateral hypothalamic area. 4. The passage of leptin across the blood–brain barrier and the chemical mediators of the action of leptin in the hypothalamus are discussed.     

Circumventricular Organs: Gateways to the Brain Axonal Projections From The Organum Vasculosum Lamina Terminalis To The Supraoptic Nucleus: Functional Analysis And Presynaptic Modulation

1. The rat organum vasculosum lamina terminalis (OVLT) contains GABA‐ and glutamate‐releasing neurons that project directly to magnocellular neurosecretory cells (MNC) in the supraoptic nucleus. 2. Changes in osmolality over the OVLT in hypothalamic explants cause proportional changes in firing in MNC through corresponding changes in the frequency of spontaneous glutamatergic excitatory post‐synaptic potentials without affecting GABAergic inhibitory post‐synaptic potentials. 3. Exogenously applied atrial natriuretic peptide inhibits the osmotic control of MNC by causing a decrease in the amount of glutamate released provoked by action potentials originating from OVLT neurons.     

COMPARATIVE NEUROANATOMY OF ANGIOTENSIN II RECEPTOR LOCALIZATION IN THE MAMMALIAN HYPOTHALAMUS

1. The distribution of angiotensin II (AII) receptor binding sites in the hypothalamus of rat, rabbit, sheep and human was determined by in vitro autoradiography using 125I-[Sar1,Ile8]-AII as radioligand. 2. High receptor binding levels were observed in the continuum of tissue comprising the anterior wall of the third ventricle, including the subfornical organ, the median pre-optic nucleus and the organum vasculosum of the lamina terminalis. 3. High levels of binding sites were also found in the paraventricular and supra-optic nuclei, the median eminence and the arcuate nucleus. 4. These findings demonstrate sites in the hypothalamus of rat, rabbit, sheep and human where AII could exert its known actions on fluid and electrolyte balance, pituitary hormone release and cardiovascular function.     

BLOCKADE OF ANGIOTENSIN CONVERTING ENZYME IN CIRCUMVENTRICULAR ORGANS OF THE BRAIN AFTER ORAL LISINOPRIL ADMINISTRATION DEMONSTRATED BY QUANTITATIVE IN VITRO AUTORADIOGRAPHY

1. To elucidate the central effect of lisinopril, a new angiotensin converting enzyme (ACE) inhibitor, ACE localization and levels were followed in the brain of Sprague-Dawley rats by quantitative in vitro autoradiography after administration of the drug. 2. Following acute lisinopril (10 mg/kg p.o.) treatment, serum ACE activity was acutely reduced, but returned to normal by 24 h. 3. Levels of ACE in most parts of the brain, including the basal ganglia and choroid plexus of all ventricles were not affected by lisinopril. Lisinopril inhibited brain ACE in the subfornical organ and organum vasculosum of the lamina terminalis, circumventricular organs, where the blood brain barrier is deficient. These regions are rich in ACE and angiotensin II receptors, and are known targets for angiotensin II-induced effects on fluid, electrolyte and blood pressure homeostasis. 4. These observations indicate that quantitative in vitro autoradiography is a powerful method to study the access of drugs to the central nervous system. 5. This study shows that blood brain barrier plays an important role in limiting the penetration of lisinopril into the central nervous system. The circumventricular organs may be important targets for ACE inhibitors.     

Circumventricular organs: definition and role in the regulation of endocrine and autonomic function

1. The circumventricular organs (CVO) are structures that permit polypeptide hypothalamic hormones to leave the brain without disrupting the blood-brain barrier (BBB) and permit substances that do not cross the BBB to trigger changes in brain function. 2. In mammals, CVO include only the median eminence and adjacent neurohypophysis, organum vasculosum lamina terminalis, subfornical organ and the area postrema. 3. The CVO are characterized by their small size, high permeability and fenestrated capillaries. The subcommissural organ is not highly permeable and does not have fenestrated capillaries, but new evidence indicates that it may be involved in the hypertension produced by aldosterone acting on the brain. 4. Feedback control of corticotropin-releasing hormone (CRH) secretion is exerted by free steroids diffusing into the brain, but substances such as cytokines and angiotensin II act on CVO to produce increases in CRH secretion. Gonadal steroids also diffuse into the brain to regulate gonadotrophin-releasing hormone secretion. Thyrotropin-releasing hormone secretion is regulated by thyroid hormones transported across cerebral capillaries. However, CVO may be involved in the negative feedback control of growth hormone and prolactin secretion.     

Neuroanatomical specificity of the circuits controlling sympathetic outflow to different targets

1. Despite the emerging framework that central neural pathways controlling the activity of the sympathetic nervous system are capable of producing highly selective responses, the specific neural pathways governing different sympathetic outflows are poorly understood. 2. Anatomical studies suggest that five brain areas, namely the rostral ventrolateral medulla, the rostral ventromedial medulla, the caudal raphe nuclei, the region containing the A5 noradrenergic neurons and the paraventricular hypothalamic nucleus, provide dominant supraspinal innervation of sympathetic preganglionic neurons. 3. The anatomical parcellation of different functions within and among these cell groups is uncertain. However, recent studies using transynaptic retrograde labelling of neural pathways connected to various sympathetic targets suggest that the circuits controlling these different targets may be partially distinct. Similarly, anatomical studies relying on stimulus-evoked expression of immediate early genes, such as c-fos, suggest that different sympathetic responses may be controlled by distinct, neural circuits. 4. Thus, although many similarities exist in the anatomical circuits innervating different sympathetic targets, possibly supporting the orchestration of global sympathetic responses, differences are also discernible.     

Central inhibition of AT1receptors by eprosartan--in vitro autoradiography in the brain.

All components of the renin-angiotensin system have been demonstrated in the brain and AT1 receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT1 receptor antagonists, which are increasingly used in the treatment of arterial hypertension and chronic heart failure, have the potential to mediate action via the central renin-angiotensin system. Therefore, we tested the in vivo access of the non-peptide AT1 receptor antagonist, eprosartan (30 and 60 mg per kg of body weight (BW) for 4 weeks, i.p. administered by osmotic minipumps), to angiotensin II receptors in the rat brain by in vitro autoradiography with 125I- (Sar1- Ile8) angiotensin II as a ligand. Eprosartan significantly increased plasma renin activity by four-fold and six-fold at doses of 30 and 60 mg x kg(-1), respectively (P< 0.05 vs CTRL). In the brain, eprosartan produced a dose-dependent inhibition of AT receptor binding in the median cerebral artery ( 850 +/- 249 and 650 +/- 106 vs 1072 +/- 116 dpm x mm(-2) of CTRL; P< 0.05). Furthermore, eprosartan inhibited angiotensin II receptor binding in discrete brain areas, which express exclusively, or predominantly, AT1 receptors both outside and within the blood-brain barrier, such as the paraventricular nucleus ( 180 +/- 47 and 130 +/- 18 vs 545 +/- 99 dpm x mm(-2)of CTRL; P< 0.05), the subfornical organ ( 106 +/- 26 and 112 +/- 17 vs 619 +/- 256 dpm x mm(-2)of CTRL; P< 0.05), and the organum vasculosum laminae terminalis ( 461 +/- 110 and 763 +/- 136 vs 1033 +/- 123 dpmx mm(-2)of CTRL; P< 0.05). These results emphasize that eprosartan readily crosses the blood-brain barrier in vivo and selectively inhibits binding to AT1 receptors in specific brain nuclei. The modulation of central regulatory mechanisms might contribute to AT1 receptor antagonists overall therapeutic efficacy in cardiovascular disease.     

Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions

1. The long-term level of arterial pressure is dependent on the relationship between arterial pressure and the urinary output of salt and water, which, in turn, is affected by a number of factors, including renal sympathetic nerve activity (RSNA). In the present brief review, we consider the mechanisms within the brain that can influence RSNA, focusing particularly on hypothalamic mechanisms. 2. The paraventricular nucleus (PVN) in the hypothalamus has major direct and indirect connections with the sympathetic outflow and there is now considerable evidence that tonic activation of the PVN sympathetic pathway contributes to the sustained increased level of RSNA that occurs in conditions such as heart failure and neurogenic hypertension. The tonic activity of PVN sympathetic neurons, in turn, depends upon the balance of excitatory and inhibitory inputs. A number of neurotransmitters and neuromodulators are involved in these tonic excitatory and inhibitory effects, including glutamate, GABA, angiotensin II and nitric oxide. 3. The dorsomedial hypothalamic nucleus (DMH) also exerts a powerful influence over sympathetic activity, including RSNA, via synapses with sympathetic nuclei in the medulla and, possibly, also other brainstem regions. The DMH sympathetic pathway is an important component of the phasic sympathoexcitatory responses associated with acute stress, but there is no evidence that it is an important component of the central pathways that produce long-term changes in arterial pressure. Nevertheless, it is possible that repeated episodic activation of this pathway could lead to vascular hypertrophy and, thus, sustained changes in vascular resistance and arterial pressure. 4. Recent studies have reactivated the old debate concerning the possible role of the baroreceptor reflex in the long-term regulation of sympathetic activity. Therefore, central resetting of the baroreceptor-sympathetic reflex may be an important component of the mechanisms causing sustained changes in RSNA. However, little is known about the cellular mechanisms that could cause such resetting.     

Autoradiographic localization of V1 vasopressin binding sites in rat brain and kidney

Monoiodination of the V1 vasopressin antagonist [Mca1,Sar7]AVP did not alter its high-affinity binding to liver plasma membranes. Monoradioiodinated [Mca1,125I-Tyr2,Sar7]AVP was therefore used to label V1-specific binding sites in the rat brain and kidney. The accumbens nucleus, the septal nucleus, the central amygdala, the bed nucleus of the stria terminalis, the stigmoid hypothalamic nucleus and the nucleus of the solitary tract exhibited specific labeling with both the radioiodinated V1 antagonist and tritiated AVP. Of the circumventricular structures only the choroid plexi and the area postrema showed V1-specific binding sites. The subfornical organ and hypothalamic loci of AVP synthesis such as the paraventricular nucleus, the supraoptic nucleus and the suprachiasmatic nucleus were not marked by the V1 antagonist while bearing [3H]AVP binding sites. As demonstrated by HPLC and binding to liver plasma membranes, the radiolabeled antagonist remained intact during tissue incubation. In addition to renal cortical and medullary [3H]AVP binding sites, medullary tubular and vascular structures could be labeled with the V1 antagonist, indicating the presence of both V1 and V2 AVP receptor subtypes in the rat kidney.     

LONG-TERM SYMPATHO-EXCITATORY EFFECT OF ANGIOTENSIN II: A MECHANISM OF SPONTANEOUS AND RENOVASCULAR HYPERTENSION

1. The peptide hormone angiotensin II (AngII) is acknowledged to be an important factor in the pathophysiology of hypertension. This is particularly the case in hypertension caused by luminal narrowing of one renal artery, (i.e. renovascular hypertension). The primary mechanism by which AngII raises blood pressure, however, is disputed. Strong arguments can be made supporting either vascular contraction, effects on renal excretion of sodium and water, or trophic actions on cardiovascular structures as the key element. In this paper I review evidence that AngII influences blood pressure by modulating autonomic nervous system activity. Modulation can occur at both the peripheral and central aspects of the autonomic system, but I focus on brain pathways involved in determining sympathetic nervous system activity. 2. Experimental and clinical investigations are cited to support the hypothesis that sympathetically mediated pressor effects are increased by both circulating and brain-derived AngII in hypertension. Recent work points specifically to sympathetic pre-motor neurons in the rostral ventrolateral medulla (RVLM) as a critical site of action of brain AngII in normoten-sive and hypertensive animals. 3. This same set of neurons appears to be an important relay in the sympatho-excitatory response to circulating AngII initiated at circumventricular organs, particularly the area pos-trema. AngII has important effects on the baroreflex. These do not mediate the sympatho-excitation elicited by circulating AngII, but rather mask its expression. 4. Substantial data support the hypothesis that increased blood concentrations of AngII in renovascular hypertension elevate blood pressure by causing neurogenic vasoconstriction mediated through the area postrema and RVLM.