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.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: 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 AT₁ antagonist losartan injected into the 4V. These results suggest that mainly AT₁ 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 AT₁ receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT₁ 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.

     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ANGIOTENSIN II AND THE ADRENAL

• 1 Angiotensin II (AngII) evokes a variety of physiological responses in the adrenal gland. It is the major regulator of aldosterone secretion, in the medulla it enhances catecholamine release and it exerts trophic effects in the adrenal and stimulates growth factor secretion.
• 2 Angiotensin II acts via binding to specific receptors, located on the plasma membrane. Two pharmacologically distinct AngII receptor subtypes, type 1 (AT₁) and type 2 (AT₂) receptors, have been identified using the non-peptide antagonists Dup753 and PD 123177, respectively, and cDNA encoding each type have been identified.
• 3 In the adrenal, the AT₁ receptor modulates all the known biological effects of AngII. The expression of the AT₁ receptor is modulated at the mRNA and protein levels by many factors: conditions that increase levels of AngII (low sodium diet, renovascular hypertension, AngII infusion) up-regulate AT₁ receptor mRNA levels and binding and increase aldosterone secretion.
• 4 A tissue renin-angiotensin system has been found in the adrenal, suggesting an important paracrine role for AngII in aldosterone regulation.
• 5 The possible involvement of AT₁ receptors in human disease has been investigated by examining the role of AngII receptors in adrenal tumours. Binding and gene expression studies have shown that AngII receptors are abundantly expressed in aldosterone-producing adenoma (APA).
• 6 Densitometric analysis of AT₁ expression in APA showed no significant differences compared with normal and nontumorous adrenal. In addition, no mutations in the coding sequence of the AT₁ receptor have been found to date in adrenal tumours.

     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR MECHANISMS OF ANGIOTENSIN II (AT1a) RECEPTOR ENDOCYTOSIS

• 1 Angiotensin II (AngII) initiates a variety of cellular responses through activation of type 1 (AT₁; with subtypes AT_1a and AT_1b) and type 2 (AT₂) cell surface angiotensin receptors. Both AT₁ and AT₂ receptors couple to heterotrimeric guanyl nucleotide binding proteins (G-proteins) and generate intracellular signals following recognition of extracellular AngII, but only AT₁ is targeted for the rapid ligand-stimulated endocytosis (internalization) typical of many plasma membrane receptors.
• 2 AT₁ endocytosis proceeds through clathrin-coated pits and is independent of G-protein coupling which predicts that the AngII-AT₁ receptor complex attains a conformation necessary for interaction with the endocytotic machinery, but separate from receptor signalling activation.
• 3 The function of AT₁ endocytosis and the reason for the disparity between AT₁ and AT₂ endocytosis is not fully appreciated, but the latter probably reflects differences in the primary amino acid sequence of these two receptor types.
• 4 For many receptors that undergo internalization, it has been established that internalization motifs (2–6 amino acids, often incorporating crucial tyrosine and hydrophobic amino acids) within the cytoplasmic regions of the receptor mediate the selective recruitment of activated receptors into clathrin-coated pits and vesicles.
• 5 Mutagenesis studies on the AT_1a receptor, aimed at identifying such motifs, reveal that sites within the third cytoplasmic loop and the cytoplasmic carboxyl terminal region are important for AngII-stimulated AT_1a receptor endocytosis.

     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PRESENCE OF ANGIOTENSIN II AT2 RECEPTOR BINDING SITES IN THE ADVENTITIA OF HUMAN KIDNEY VASCULATURE

• 1 Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized by in vitro autoradiography using the AngII receptor subtype-selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol.
• 2 High densities of AngII AT₁ receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT₁ receptor binding is localized in the proximal convoluted tubules.
• 3 AT₂ receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter- and intra-lobular arteries, and in the renal capsule.
• 4 In the major renal artery, AT₁ receptor binding is abundant in the media and adventitia, while AT₂ receptor binding is observed mainly in the adventitia.
• 5 At the light microscopic level using emulsion autoradiography, AT₁ receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter- and intra-lobular arteries, intense AT₂ receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding.
• 6 These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT¹ predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT₂ predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT₂ receptor binding sites in the adventitia of adult human kidney vessels remains to be elucidated.

     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ENDOGENOUS ANGIOTENSIN II LEVELS AND THE MECHANISM OF ACTION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR TYPE 1 ANTAGONISTS

• 1 Modification of endogenous angiotensin II (AngII)-mediated processes by inhibitors of the angiotensin-converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT₁) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels.
• 2 Both ACE inhibitors and AT₁ receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT₁ receptor antagonists produce incomplete blockade of AT₁ receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist.
• 3 The effects of ACE inhibitors and AT₁ receptor antagonists on AngII levels show tissue specificity. Angiotensin II-mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT₁ receptor antagonists. The inhibition of AngII-mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT₁ receptor antagonists on blood pressure and other aspects of cardiovascular function and structure.
• 4 Combination of an ACE inhibitor with an AT₁ receptor antagonist prevents the rise in plasma AngII levels that occurs with AT₁ receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII-mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT₁ receptor antagonism results in superior clinical outcomes.

     

Neural pathways from the lamina terminalis influencing cardiovascular and body fluid homeostasis

1. The lamina terminalis, a region of the brain with a high concentration of angiotensin AT1 receptors, consists of three distinct nuclei, the median preoptic nucleus, the subfornical organ and organum vasculosum of the lamina terminalis (OVLT). These latter two regions lack a blood-brain and detect changes in plasma angiotensin (Ang) II concentration and osmolality. 2. Efferent neural pathways from the lamina terminalis to the hypothalamic paraventricular and supraoptic nuclei mediate vasopressin secretion in response to plasma hypertonicity and increased circulating levels of AngII. 3. Studies using the neurotropic virus pseudorabies, which undergoes retrograde transynaptic neuronal transport following injection into peripheral sites, show that neurons in the lamina terminalis have efferent polysynaptic neural connections to the peripheral sympathetic nervous system. Some of these neurons have been shown to have polysynaptic connections to the kidney and to express AT1 receptor mRNA. We propose that circulating AngII acts at AT1 receptors in the subfornical organ and OVLT to influence the sympathetic nervous system. It is likely that the neural pathway subserving this influence involves a synapse in the hypothalamic paraventricular nucleus. 4. The lamina terminalis may exert an inhibitory osmoregulatory influence on renin secretion by the kidney. This osmoregulatory influence may be mediated by inhibition of renal sympathetic nerve activity and appears to involve a central angiotensinergic synapse. 5. The lamina terminalis exerts an osmoregulatory influence on renal sodium excretion that is independent of the renal nerves and is probably hormonally mediated.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: FUNCTIONS OF ANGIOTENSIN PEPTIDES IN THE ROSTRAL VENTROLATERAL MEDULLA

• 1 It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action.
• 2 The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non-cardiovascular neurons in this region.
• 3 It is known that pressor neurons in the rostral VLM include both catecholamine and non-catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified.
• 4 It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.

     

Role of angiotensin AT2 receptors in natriuresis: Intrarenal mechanisms and therapeutic potential

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ANGIOTENSIN II ACTIVATES PRESSOR AND DEPRESSOR SITES OF THE PONTOMEDULLA THAT REACT TO GLUTAMATE

1. In cats anaesthetized with a mixture of α-chloralose (40 mg/kg) and urethane (400 mg/kg) and in rats anaesthetized with a mixture of α-chloralose (60 mg/kg) and urethane (800 mg/kg), changes in systemic arterial pressure (SAP), heart rate (HR) and sympathetic activities of vertebral (VNA) and renal (RNA) nerves were determined following the micro-injection of angiotensin II (AngII; 0.16 mmol/L; 50 nL) into the pressor and depressor sites of the pontomedulla previously reacted to a microinjection of monosodium l -glutamate (Glu; O.1 mol/L; 50 nL). Pressor sites included gigantocellular tegmental field (FTG) and dorsal medulla (DM) and rostral ventrolateral medulla (VLM). The depressor site was the caudal VLM (CVLM). The effects of losartan (1 mmol/L; 50 nL), a specific AT₁ receptor non-peptide antagonist for AngII, on responses induced by AngII in the VLM, DM and CVLM were also determined. 2. In 30% of pressor sites in the FTG, 55% in the VLM and 67% in the DM and in 76% of depressor sites in the CVLM previously exposed to Glu, microinjection of AngII to the same site produced pressor or depressor responses similar to that of Glu, but smaller in magnitude, particularly in the pressor VLM. Changes in both VNA and RNA induced by AngII were also smaller than those induced by Glu, particularly RNA from DM activation. 3. In the dorsal motor nucleus of the vagus, AngII, as Glu, produced marked bradycardia, but again this was smaller in magnitude than the bradycardia produced by Glu. 4. In rats, in the DM near or around the nucleus of the solitary tract where Glu increased SAP, microinjection of AngII (0.8 mmol/L; 60 nL) produced a depressor response, while the microinjection of 1.6 mmol/L (60 nL) AngII produced a pressor response. 5. Losartan blocked the increases in SAP induced by AngII in the VLM and DM. Decreases in SAP induced by AngII in the CVLM, however, were only slightly decreased by losartan. 6. Our data suggest that a significant portion of pressor and depressor sites of the pontomedulla contain neurons responsive to both AngII and Glu. In neurons in the VLM and DM, AngII produced pressor responses that were primarily mediated through AT₁ receptors, while the depressor actions of AngII in the CVLM were not mediated by AT₁ receptors.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR DETERMINANTS OF PEPTIDE AND NON-PEPTIDE BINDING TO THE AT1 RECEPTOR

• 1 Several residues critically involved in AT₁ receptor ligand-binding and activation have now been identified based on mutational and biochemical studies.
• 2 Asp²⁸¹ and Lys¹⁹⁹ of the rat AT₁ receptor ion-pair with Arg² and the Phe³ α-COOH of angiotensin II (AngII), respectively, and the Asp²⁸¹/Arg² interaction is critical for full agonist activity.
• 3 Agonist activity of AngII also requires an interaction of the Phe² side chain with His²⁵⁶, which is achieved by docking of the α-COOH with Lys¹⁹⁹. Non-peptide agonists interact with Lys¹⁹⁹ and His²⁵⁶ in a similar fashion.
• 4 The crucial acid pharmacophores of AngII and the non-peptide antagonist, Iosartan, appear to occupy the same space within the receptor pocket. Binding of the tetrazole anion moiety of losartan involves multiple contacts, such as Lys¹⁹⁹ and His²⁵⁶. However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine-aromatic interaction.
• 5 Asp¹ of AngII forms an ion-pair with His¹⁸³, which stabilizes the receptor-bound conformation of AngII but is not critical for receptor activation.
• 6 These interactions and the involvement of other residues in stabilizing the wild-type receptor conformation or in receptor/G-protein coupling are considered here.
• 7 Despite these insights, considerable effort is still needed to elucidate how ligand binding induces receptor activation, what determines the specificity of AT₁ receptor coupling to multiple G-proteins and the in vivo role of receptor down-regulation.

     

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.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ANGIOTENSIN RECEPTORS AND DEVELOPMENT: THE KIDNEY

• 1 This brief review examines the evidence that angiotensin II (AngII) is essential for kidney development.
• 2 Several components of the renin-angiotensin system (RAS) are detected in the foetal kidney early in development.
• 3 Angiotensin II is essential for normal foetal and neonatal renal function.
• 4 Angiotensin II receptors transduce important signals leading to growth and development.
• 5 Angiotensin receptor subtypes show spatial and temporal specificity of localization throughout renal development.
• 6 Angiotensin converting enzyme (ACE) inhibition or AngII receptor blockade (specifically AT₁ subtype blockade) results in functional and structural abnormalities of the developing kidney in both experimental and clinical situations.
• 7 While chronic postnatal RAS blockade in rats is associated with structural damage to tubules and blood vessels of the kidney, reports differ on whether treatment also affects glomerular induction and growth.
• 8 In metanephric organ culture, glomerular induction proceeds despite AngII receptor blockade.
• 9 In summary, the evidence suggests that AngII is not essential for nephron induction and glomerular development in the rat kidney. However, AngII is essential for normal growth and development of renal tubules and vasculature.

     

CNS PATHWAYS MEDIATING CARDIOVASCULAR REGULATION OF VASOPRESSIN

1. The release of vasopressin from the neurohypophysial terminals of hypothalamic magnocellular neurosecretory neurons is subject to regulation by peripheral baroreceptors, cardiopulmonary volume receptors and circulating angiotensin II. Information from these sources is transmitted through different pathways to achieve different influences on the excitability of the vasopressin-secreting cells. 2. A brief increase in arterial pressure, sufficient to activate baroreceptors, is associated with a transient and selective GABAergic inhibition of these neurosecretory neurons, achieved through a multisynaptic pathway that involves ascending catecholaminergic fibres and neurons in the diagonal band of Broca. A decrease in arterial pressure activates peripheral low volume receptors and initiating neural inputs that result in an increase in the excitability of vasopressin-secreting neurons, achieved via pathways that include direct projections from caudal ventrolateral medulla A1 neurons. 3. Hypotension also releases renal renin and leads to the formation of angiotensin II; binding of this hormone to AT₁ receptors on subfornical organ neurons promotes activation of a central angiotensinergic input that evokes a predominantly excitatory effect on vasopressin neurons.     

Protective arms of the renin–angiotensin‐system in neurological disease

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The role of oxidative stress in renovascular hypertension

1. There is mounting evidence that increased oxidative stress and sympathetic nerve activity play important roles in renovascular hypertension. In the present review, we focus on the importance of oxidative stress in two distinct populations of neurons involved with cardiovascular regulation: those of the rostral ventrolateral medulla (RVLM) and those of the paraventricular nucleus of the hypothalamus (PVN) in the maintenance of sympathoexcitation and hypertension in two kidney–one clip (2K1C) hypertensive rats. Furthermore, the role of oxidative stress in the clipped kidney is also discussed. 2. In the studies reviewed in this article, it was found that hypertension and renal sympathoexcitation in 2K1C rats were associated with an increase in Angiotensin II type one receptor (AT₁) expression and in oxidative markers within the RVLM, PVN and in the clipped kidneys of 2K1C rats. Furthermore, acute or chronic anti‐oxidant treatment decreased blood pressure and sympathetic activity, and improved the baroreflex control of heart rate and renal sympathetic nerve activity in 2K1C rats. Tempol or vitamin C administration in the RVLM, PVN or systemically all reduced blood pressure and renal sympathetic activity. Cardiovascular improvement in response to chronic anti‐oxidant treatment was associated with a downregulation of AT₁ receptors, as well as oxidative markers in the central nuclei and clipped kidney. 3. The data discussed in the present review support the idea that an increase in oxidative stress within the RVLM, PVN and in the ischaemic kidney plays a major role in the maintenance of sympathoexcitation and hypertension in 2K1C rats.     

The brain angiotensin IV/AT4 receptor system as a new target for the treatment of Alzheimer's disease

The brain renin‐angiotensin system (RAS) regulates several physiologies including blood pressure, body sodium and water balance, cyclicity of reproductive hormones and related sexual behaviors, and the release of pituitary gland hormones. These physiologies are under the control of the angiotensin II (AngII)/AT₁ receptor subtype system. The AngII/AT₂ receptor subtype system is expressed during fetal development and is less abundant in the adult. This system appears to oppose growth responses facilitated by activation of the AT₁ receptor. There is a growing list of nontraditional physiologies mediated by the most recently discovered angiotensin IV (AngIV)/AT₄ receptor subtype system that include the regulation of blood flow, modulation of exploratory behaviors, involvement in stress responses and seizure, and a role in learning and memory acquisition. There is evidence to support an inhibitory influence by AngII, and a facilitory role by AngIV, on neuronal firing rate, long‐term potentiation, and associative and spatial learning and memory. These findings suggest an important role for the RAS, and the AT₄ receptor in particular, in normal cognitive processing and provide the stimulus for developing drugs that penetrate the blood‐brain barrier to interact with this brain receptor in the treatment of dysfunctional memory. Drug Dev Res 70: 472–480, 2009. © 2009 Wiley‐Liss, Inc.     

Angiotensin‐II type 1 receptor (AT1R) and alpha‐1D adrenoceptor form a heterodimer during pregnancy‐induced hypertension

1 Pregnancy courses with low response to angiotensin II and adrenergic agonists. In preeclampsia, both effects are reverted. It is known that angiotensin II regulates adrenergic system. It is not known, however, the interaction between both systems receptors. 2 Our aim was to study if AT₁R and α1D adrenoceptor heterodimerize in preeclampsia. 3 We used subrenal aorctic coarctation in pregnant rats. Aortic tissues were prepared for confocal imaging and coimmunoprecipitated for α1D and AT₁ receptors. 4 We found that AT₁R and α1D adrenoceptor heterodimerize in both, healthy and preeclamptic groups. In healthy pregnant rats, heterodimer is barely detected. In preeclamptic rats however, we found higher heterodimerization. 5 These results suggest that AT₁R and α1D ‐adrenoceptor may form heterodimers, and may play a role in preeclampsia.     

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.