Central Regulation Of Blood Pressure Research Articles

In Vivo Mutation of the α2A-Adrenergic Receptor by Homologous Recombination Reveals the Role of This Receptor Subtype in Multiple Physiological Processes

α2-Adrenergic receptors (α2ARs) are broadly associated with inhibitory actions of norepinephrine and epinephrine. Studies with drugs designed as α2AR agonists and antagonists have shown that α2ARs participate in a wide range of central nervous system activities, including central regulation of blood pressure, sedation and analgesia, control of affect, and modulation of pituitary hormone release. In the periphery, α2ARs inhibit neurotransmitter release from peripheral nervous system neuronal terminals, inhibit insulin secretion by pancreatic β cells, and participate in the regulation of water and electrolyte balance in the kidney. The α2ARs that elicit these varied responses represent a structural and functional family of receptor subtypes defined by pharmacological measurements and molecular cloning. Interest of studies has been to establish a mouse line that expressed a mutant α2AAR receptor with selectively altered signal transduction capabilities. Studies have shown that mutation of the highly conserved aspartate residue at position 79 in the α2AAR to asparagine (D79N) results in a receptor that is uncoupled from a single signaling pathway. In this purpose the two-step “hit and run” gene-targeting approach is successfully used in mouse embryonic stem cells to establish a mouse line with this D79N α2AAR mutation. Such studies reveal that the α2AAR subtype has a role central to several of the clinically desirable effects of α2AR agonists, suggesting that these functions cannot be separated by administering subtype-specific drugs. Null mutation of the α2BAR subtype has revealed that this subtype mediates the increase in blood pressure immediately following α2AR agonist administration. Thus, drugs that are selective for the α2AAR subtype relative to the α2BAR subtype may hold promise as improved antihypertensive agents. Sedative side effects might be eliminated if high-affinity partial agonists are developed, especially if higher receptor occupancy is needed to evoke sedation in contrast to hypotension.

Evidence that A 2a and not A 2b purinoceptors are coupled to production of nitric oxide in the central regulation of blood pressure

In a previous study we reported that nitric oxide (NO) partially mediates centrally the decrease of arterial blood pressure induced by adenosine A 2 subtype receptor stimulation. The present study confirms the earlier suggestion and shows that in adult male normotensive anaesthetized rats 5′- N-ethylcarboxamidoadenosine (NECA), a non-selective adenosine receptor agonist, centrally injected induced a significant decrease of arterial blood pressure. Moreover, the observation that intracerebroventricular (i.c.v.) administration of N ω-nitro- l-arginine methyl ester ( l-NAME), a NO synthase inhibitor, +8-(3-chlorostyryl)-caffeine (CSC), antagonist of A 2a receptors, did not reduce furthermore the hypotensive effect induced by NECA injection, demonstrated that NO is involved only via A 2a and not via A 2b adenosine subtype receptors in the central regulation of blood pressure.

Antisense Inhibition of the Brain Kallikrein-Kinin System

We used antisense oligodeoxynucleotide (ODN) strategy, based on interference of information flow from gene to protein, to determine the role of kininogen and bradykinin B2 receptor genes in the pathogenesis of genetic hypertension in rats. Mean blood pressure of 9-week-old spontaneously hypertensive rats (SHR) increased 4 hours after acute intracerebroventricular injection of synthetic 18-mer antisense ODNs targeting the translation initiation codon of kininogen mRNA (from 164 +/- 5 to 181 +/- 4 mm Hg, P < .01) or bradykinin B2 receptor mRNA (from 161 +/- 5 to 185 +/- 8 mm Hg, P < .01) and then returned to basal levels within 24 hours. Prolonged vasopressor effects were observed after repeated injections of antisense ODN targeting kininogen mRNA. Antisense ODNs to kininogen and B2 receptor mRNAs increased blood pressure of normotensive Wistar-Kyoto rats only slightly compared with SHR (from 116 +/- 3 to 124 +/- 1 and from 116 +/- 2 to 126 +/- 4 mm Hg, respectively; P < .05). Cardiovascular responses were confirmed by the use of antisense ODNs targeted to bind to different non-overlapping regions of kininogen or B2 receptor mRNA. Microinjection of antisense ODN to B2 receptor mRNA into the nucleus tractus solitarii increased mean blood pressure in SHR and prevented the vasodepressor effect induced by intranuclear microinjection of bradykinin. No significant change in mean blood pressure was induced in either strain by intravenous injection of antisense ODNs or by central injection of sense or scrambled ODNs. A strong fluorescent signal was detected at the level of the hippocampus, thalamus, hypothalamus periventricularis, midbrain, and cerebrum 1 hour after central injection of fluorescein isothiocyanate-conjugated antisense ODNs. Kininogen levels were significantly lower in the brain of rats given intracerebroventricular antisense kininogen ODN compared with controls. Our results indicate that the brain kallikrein-kinin system plays a role in the central regulation of blood pressure and suggest that this system may exert a protective action against further elevations of blood pressure levels in SHR.

Adrenomedullin, a novel vasoactive hormone, binds to mouse astrocytes and stimulates cyclic AMP production

We have examined the effects of adrenomedullin (AM), a novel hypotensive peptide first isolated from human pheochromocytoma, on receptor binding and cyclic AMP (cAMP) generation in primary cultures of mouse astrocytes. Competition binding studies showed that rat adrenomedullin (rAM) displaced the specific binding of [125I]rAM in a dose-dependent manner, with an estimated IC50 of 33 nM. Rat calcitonin gene-related peptide (rCGRP), which interacts with AM receptors in some vascular tissues, did not produce significant displacement of [125I]rAM at concentrations up to 3.3 μM. rAM stimulated cAMP production in mouse astrocytes in a dose-dependent manner, with an EC50 of 74 nM and a maximal stimulatory concentration of 1 μM. CGRP8–37, a CGRP receptor antagonist, failed to inhibit the cAMP response to rAM, although it attenuated CGRP-stimulated cAMP production. These data indicate that cultured mouse astrocytes possess specific AM receptors which are coupled to adenylate cyclase but do not interact with CGRP. AM may function as a neuropeptide and may play a role in the central regulation of blood pressure and body fluid balance. © 1996 Wiley-Liss, Inc.

Modification of cardiovascular response of adenosine A 1 receptor agonist by cyclic AMP in the spinal cord of the rats

This study was performed to investigate the influence of the spinal adenosine A 1 receptors on the central regulation of blood pressure (BP) and heart rate (HR), and to define whether its mechanism is mediated by cyclic AMP (cAMP) or cyclic GMP (cGMP). Intrathecal (i.t.) administration of drugs at the thoracic level were performed in anesthetized, artificially ventilated male Sprague-Dawyley rats. Injection (i.t.) of adenosine A 1 receptor agonist, N 6-cyclohexyladenosine (CHA; 1, 5 and 10 nmol) produced dose dependent decrease of BP and HR. Pretreatment with a cAMP analogue, 8-bromo-cAMP, attenuated the depressor and bradycardiac effects of CHA (10 nmol), but not with cGMP analogue, 8-bromo-cGMP. These result suggest that adenosine A 1 receptor in the spinal cord plays an inhibitory role in the central cardiovascular regulation and that this depressor and bradycardiac actions are mediated by cAMP.

Adrenomedullin, a novel vasoactive hormone, binds to mouse astrocytes and stimulates cyclic AMP production.

We have examined the effects of adrenomedullin (AM), a novel hypotensive peptide first isolated from human pheochromocytoma, on receptor binding and cyclic AMP (cAMP) generation in primary cultures of mouse astrocytes. Competition binding studies showed that rat adrenomedullin (rAM) displaced the specific binding of [125I]rAM in a dose-dependent manner, with an estimated IC50 of 33 nM. Rat calcitonin gene-related peptide (rCGRP), which interacts with AM receptors in some vascular tissues, did not produce significant displacement of [125I]rAM at concentrations up to 3.3 microM. rAM stimulated cAMP production in mouse astrocytes in a dose-dependent manner, with an EC50 of 74 nM and a maximal stimulatory concentration of 1 microM. CGRP8-37, a CGRP receptor antagonist, failed to inhibit the cAMP response to rAM, although it attenuated CGRP-stimulated cAMP production. These data indicate that cultured mouse astrocytes possess specific AM receptors which are coupled to adenylate cyclase but do not interact with CGRP. AM may function as a neuropeptide and may play a role in the central regulation of blood pressure and body fluid balance.

Brain angiotensin and circulatory control.

1. Components of the renin-angiotensin system (RAS) are found in the brain; both outside and inside the blood-brain barrier. 2. Almost all of the classical actions of the brain RAS are attributable to angiotensin (Ang) II and mediated by AT1 receptors. 3. Circumventricular organs (CVO), which lack the blood-brain barrier, are rich in AngII receptors and monitor circulating AngII levels. In vivo binding studies suggest that the CVO are also accessible to cerebrospinal fluid-derived AngII. 4. The median preoptic nucleus, paraventricular hypothalamic nucleus, supraoptic nucleus, nucleus tractus solitarius and ventrolateral medulla are inside the blood-brain barrier and are sites of action of brain AngII. In these nuclei, AngII seems to act as an excitatory neurotransmitter or neuromodulator. 5. Actions of AngII in the brain, both inside and outside the blood-brain barrier, are implicated in the central regulation of blood pressure and sympathetic outflow, release of hypothalamic and pituitary hormones and renal sodium handling. 6. Alterations in the activity of brain AngII may be involved in the mechanisms of some types of hypertension.

Intrathecal administration of sodium nitroprusside, a nitric oxide donor, increases blood pressure in anesthetized rats

The present study was performed to investigate the role of spinal nitric oxide (NO) in the central regulation of blood pressure (BP). Experiments were carried out in anesthetized artificially ventilated male Wistar rats. Intrathecal (i.t.) administration of drugs was made at the thoracic spinal level. I.t. injection of a NO donor, sodium nitroprusside (SNP; 1, 5, and 15 nmol) increased BP dose-dependently. Intrathecal pretreatment of methylene blue (200 nmol) significantly attenuated the pressor response evoked by SNP (15 nmol, i.t.). I.t. administration of nitric oxide synthase inhibitor, N G-nitro- l-arginine methyl ester (100 and 1000 nmol), caused decreases in BP. These results suggest that NO plays a tonic excitatory role in the central regulation of BP in the rat spinal cord.

Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat.

Human epidemiological data show a strong association between low birth weight and hypertension in adulthood, an effect that has been ascribed to 'fetal programming'. In rats fetoplacental exposure to maternally administered dexamethasone throughout gestation reduces birth weight and produces hypertensive adult offspring, though the mechanism is unclear. Pre- and postnatal stress programmes hypothalamic-pituitary-adrenal (HPA) axis responses throughout the lifespan, an effect thought to be mediated via permanent effects on glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) gene expression in the hippocampus. Corticosteroids also have specific central effects on blood pressure control mediated by GR and MR. This study investigated corticosterone (CORT) responses to restraint stress and GR and MR gene expression in areas of the brain postulated to mediate the central effects of corticosteroids on (i) HPA axis suppression (hippocampus), and (ii) blood pressure (organ vasculosum of the lamina terminalis (OVLT), sub-commissural organ, area postrema and nucleus tractus solitarius). Pregnant Wistar rats received dexamethasone (100 micrograms/kg.day-1) or vehicle on days 15-20 of gestation. This reduced birth weight by 11%. When the offspring were 16 weeks old, blood pressure was recorded directly and plasma CORT measured basally (AM) and after 30 min restraint. GR and MR mRNA expression were determined by in situ hybridization. Blood pressure was significantly elevated in the adult offspring of dexamethasone-treated pregnancies (dexamethasone 144 +/- 2/125 +/- 2 mm Hg vs. control 133 +/- 2.7/112 +/- 2.8 mm Hg; both p < 0.01). Offspring of dexamethasone-treated pregnancies had increased basal plasma CORT (155 +/- 29 nmol/l) compared to offspring of controls (79 +/-15 nmol/l, p < 0.05), but the CORT response to stress was similar. Hippocampal neuronal GR mRNA expression was significantly lower in the offspring of dexamethasone-treated pregnancies (dentate gyrus 20% lower, CA1 15% lower; p < 0.01). Similarly, hippocampal MR gene expression was decreased in CA1 and CA2 by 24 and 25%, respectively (p < 0.05). No differences in GR or MR mRNA expression were found in the OVLT, subcommissural organ, area postrema or nucleus tractus solitarius. These findings suggest that glucocorticoid excess in the last trimester of rat pregnancy (i) is sufficient to programme offspring hypertension; (ii) also increases basal plasma CORT levels, and (iii) permanently attenuates GR and MR mRNA expression in specific hippocampal subfields. Thus, if translated into protein, may reduce sensitivity to glucocorticoid feedback and thus contribute to the CORT excess. However, hypertension in this model is unlikely to be mediated by similar changes in GR or MR gene expression in the examined areas of the brain putatively involved in the more direct central regulation of blood pressure.

Aldosterone and its mechanism of action: more questions than answers.

The physiology of the steroid hormone, aldosterone is well defined. The molecular events that mediate this response remain to be elucidated. Aldosterone binds to a specific mineralocorticoid receptor (MR) in sodium transporting epithelia. The structural determinants of ligand-binding have been explored through the analysis of steroid resistance syndromes, however, the molecular basis of resistance to aldosterone, pseudohypoaldosteronism remains an enigma. Cortisol also binds MR, access is however restricted by the enzyme 11 beta-hydroxysteroid dehydrogenase. The MR induces specific genes which regulate apical amiloride-sensitive epithelial sodium channels; the finding of activating mutations in Liddles syndrome (pseudoaldosteronism) has emphasised their key role. Such mechanisms may apply not only to the peripheral effects of aldosterone but also to the central regulation of blood pressure.

Neurally mediated syncope and serotonin reuptake inhibitors.

Serotonin (5-hydroxytryptamine or 5HT) is a neurotransmitter which appears to play a prominent role in central regulation of heart rate and blood pressure. Recent evidence suggests that the activation of cerebral serotonin receptors results in a depressor effect principally through sympatho-inhibition. Several common clinical disorders resulting in hypotension leading to syncope are neurally mediated syncope, carotid sinus hypersensitivity and orthostatic hypotension, each of which may involve a serotonergic component. This brief review provides a summary of serotonergic blood pressure regulation, as well as the initial experience with the clinical effects of the serotonin reuptake inhibitors in the therapy of the aforementioned disorders.

Why imidazoline receptor modulator in the treatment of hypertension?

The influence of the sympathetic nervous system on blood pressure control was impressively demonstrated in 1940 by bilateral excision of sympathetic nerve fibers. Thereafter, the first generation of drugs lowering blood pressure by central modulation of the sympathetic outflow through alpha 2-adrenoceptor for stimulation, such as alpha-methyldopa, guanabenz, clonidine, and guanfacine, were marketed. However, these compounds were often tolerated poorly, because they caused orthostatic hypotension, sedation, tachycardia or bradycardia, dry mouth, and reduced cardiac output. The mode of action of the second generation centrally acting antihypertensive drugs moxonidine and rilmenidine is different from that of the first generation compounds (e.g., clonidine). Contrary to clonidine, the newer drugs bind more selectively to I1-imidazoline receptors rather than to alpha 2-adrenoceptors where first-generation drugs act. The high affinity and selectivity of these two drugs for this recently discovered new receptor class make it possible to discriminate between I1-imidazoline receptor-mediated blood pressure lowering, on the one hand, and alpha 2-adrenoceptor-mediated side effects, on the other. Discrimination of the two effects was substantiated either by studies using moxonidine alone or in interaction experiments with I1-imidazoline receptor or alpha 2-adrenoceptor antagonists. The high selectivity of moxonidine at the I1-imidazoline receptor allows discrimination between alpha 2-adrenoceptors and I1-imidazoline receptors and is reflected in man by the relatively low incidence of adverse drug events during moxonidine treatment. Concentration of endazoline, a specific mediator of I1-imidazoline receptors, is elevated in some patients with essential hypertension. Modulation of I1-imidazoline receptors by moxonidine could be interpreted as antagonism with regard to the endogenous agonistic effect of the endogenous "transmitter" endazoline. On the other hand, moxonidine acted directly as an agonist at the putative I1-imidazoline receptor. Therefore, to clear the ground, characterization as well as physiological function of the mediator for imidazoline receptors seems essential. The therapeutic relevance of using drugs selective for I1-imidazoline receptors for blood pressure reduction in hypertensive patients is substantiated by the finding that in human rostral ventrolateral medulla (RVLM), which is essential in central blood pressure regulation, the relation between alpha 2-adrenoceptors and I1-imidazoline receptors is about one to ten (1:10). Reduction of a long-lasting sympathetic overdrive may avoid the deteriorating effects on the heart and peripheral circulation. These recent findings give a rational explanation for the very low incidence of sedation and the absence of respiratory depression, orthostatic hypotension, and rebound hypertension that banned the former central acting antihypertensive drugs from first-line treatment despite the advantages of central mediated blood pressure control.

Central α2-adrenoceptors and blood pressure regulation in the rat

The role of α 2-adrenoceptors in the central regulation of blood pressure has been questioned, since drugs such as clonidine stimulate both α 2-adrenoceptors and imidazoline-preferring receptors. The present work was undertaken to study the influence of α 2 D -adrenoceptors, encoded by the RG20 gene, on blood pressure in the rat. An antisense phosphodiester oligodeoxynucleotide, directed at nucleotides 4–21 of the RG20 gene, was injected in the right lateral cerebral ventricle, causing an increase in systolic blood pressure, both at 1 and 2 days after the injection, when compared to groups of control rats (injected with the sense oligodeoxynucleotide or a missense oligodeoxynucleotide or distilled water). Antisense oligodeoxynucleotides directed either at nucleotides 65–82 of the RG10 gene (encoding for α 2 C -adrenoceptors) or at nucleotides 26–43 of the RNG gene (encoding for α 2 B -adrenoceptors), failed to produce any change in blood pressure after being injected. We conclude that the α 2-adrenoceptor encoded by the RG20 gene may play a role in blood pressure regulation in the rat.

Localization of I2-Imidazoline Binding Sites on Monoamine Oxidases

Imidazoline binding sites (IBS) were proposed to be responsible for some of the pharmacological and therapeutic activities of imidazoline and related compounds and have been classified into two subtypes, I1BS and I2BS. Convergent studies attribute a role in central blood pressure regulation to the I1BS. In contrast, the function of I2BS remains unknown. In the present study, by combining biochemical and molecular biology approaches, we show that 1) microsequencing of I2BS purified from rabbit kidney mitochondria allowed the recovery of four peptide sequence stretches displaying up to 85.7% similarity with human, rat, and bovine monoamine oxidases (MAO)-A and -B; 2) I2BS and MAO displayed identical biophysical characteristics as their activities, measured by [3H]idazoxan binding and [14C]tyramine oxidation, respectively, could not be separated using various chromatographic procedures; and 3) heterologous expression of human placenta MAO-A and human liver MAO-B in yeast, inherently devoid of I2BS and MAO activities, led to the coexpression of [3H]idazoxan binding sites displaying ligand-recognition properties typical of I2BS. These results show definitely that I2BS is located on both MAO-A and -B. The fact that I2BS ligands inhibited MAO activity independently of the interaction with the catalytic region suggests that I2BS might be a previously unknown MAO regulatory site.

Antisense inhibition of hypertension in the spontaneously hypertensive rat.

Phosphorothioated antisense oligodeoxynucleotide (ASODN) targeted to angiotensinogen mRNA was administered intracerebroventricularly in spontaneously hypertensive rats to test whether angiotensinogen reduction would lower their hypertensive blood pressures. The ASODN lowers hypertensive blood pressures to normotensive levels in spontaneously hypertensive rats; sense oligodeoxynucleotide had no effect. Administration of phosphorothioated ASODN produced a prolonged duration of lowered blood pressure. Injections of ASODN at the same dose that decreased hypertension when administered centrally did not result in blood pressure decreases when administered intra-arterially. Furthermore, angiotensinogen production was decreased in the brain stem and significantly decreased in the hypothalamus of the ASODN-treated rats (P < .05), supporting the concept of centrally mediated regulation of hypertension by an overactive brain angiotensin system. To determine the distribution of centrally administered oligodeoxynucleotides, fluorescein isothiocyanate-conjugated oligodeoxynucleotides were injected directly into the lateral ventricles. One hour later, oligodeoxynucleotides were distributed throughout the lateral and third ventricles, with tissue and cellular uptake observed in discrete cells at the injection site. This indicates that the oligodeoxynucleotides are taken up rapidly by brain cells and that they permeate the areas surrounding brain nuclei involved in central blood pressure regulation and volume homeostasis. The results confirm and extend our previous study with phosphodiester ASODN and show that phosphorothioation modification increases the duration of the response and is taken up in vivo. We conclude that with modification, ASODN inhibition of angiotensinogen mRNA translation can be used for a prolonged, profound decrease in mean arterial pressure in the spontaneously hypertensive rat through a central mechanism.

C-fos expression in central cardiovascular pathways.

Injection of muscimol in the caudal ventrolateral medulla increases blood pressure and stimulates neuronal c-fos expression in the rostral ventral medulla (RVM). The blockade of c-fos expression in the RVM by antisense oligonucleotides attenuates the blood pressure response to this muscimol-induced disinhibition of the RVM and also reduces resting blood pressure. The results suggest that cardiovascular neurons in the RVM express c-fos and that the basal and stimulated expression of the c-fos gene is important in the central regulation of blood pressure.

Substance P and serotonergic inputs to sympathetic preganglionic neurons.

Sympathetic preganglionic neurons are the final central links in the sympathetic pathways that control the heart and blood vessels. The neurotransmitters present in the supraspinal pathways that control the activity of sympathetic preganglionic neurons include amino acids, amines and peptides. In this paper we discuss evidence that suggests a role for serotonin and substance P in these pathways. Both of these neurotransmitters are present in bulbospinal neurons. Our results suggest that they have an important physiological role in the central regulation of blood pressure.

Endothelin, cerebral ischaemia and infarction.

Endothelin-1 (ET-1) is a 21 aminoacid peptide with potent vasoconstrictor properties. It is synthesised and released by endothelial cells in both the peripheral and cerebral vasculature and is also localised within neurones in discrete brain areas where it may contribute to the central regulation of blood pressure. We have shown that intracisternal ET-1 in conscious rats induces a marked pressor response that is associated with an intense widespread reduction in cerebral blood flow. Subsequent studies with local application of ET-1 to the middle cerebral artery (MCA) revealed a dose dependent reversible vasoconstriction of the artery that resulted in profound reductions in local cerebral blood flow and the development of cerebral infarction. Thus abluminal application of ET-1 to the MCA offers a simple model of reversible focal cerebral ischaemia in the rat that complements the existing models of permanent MCA occlusion. The ET-1 model will help to provide new insights into the mechanisms of cerebral ischaemia and reperfusion injury, and to evaluate the usefulness of novel strategies of neuroprotection.

Different types of centrally acting antihypertensives and their targets in the central nervous system

The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex are, including both adrenergic and serotonergic pathways, as well as amino acids, as neurotransmitters. Both adrenergic and serotonergic pathways have been recognized as targets for clinically relevant, centrally acting antihypertensives, such as clonidine, guanfacine, and alpha-methyl-DOPA. The central components of the hybrid drugs urapidil and ketanserin also involve serotonergic pathways and receptors. For urapidil the stimulation of 5-HT1A-receptors is assumed to induce peripheral sympathoinhibition, whereas for ketanserin the central mechanism is unknown in detail. More recently central imidazoline (I1) receptors have been proposed as the major target for the newer antihypertensives rilmenidine and moxonidine. Clonidine, however, is assumed to be mixed I1- and alpha2-receptor agonist. The distinction between central I1- and alpha2-receptors may potentially offer the design of new antihypertensives, acting like clonidine but with fewer side effects. Finally, the amino acid pathways should be considered as potential targets for centrally acting antihypertensives. Experimental compounds on this basis are available but clinical implications appear to be very remote. In the present survey an outline is given of the various pathways, neurotransmitters, and receptors involved in the central regulation of blood pressure. The different types of centrally acting antihypertensives are subsequently discussed on this basis.

Role of interleukin 1β in the integrative mechanisms and the maintenance of body fluid homeostasis in conscious rats

Changes in the central ANF-system of renovascular hypertensive rats. The central atrial natriuretic peptides (ANF)-system was investigated in volume-dependent one-kidney, one-clip (1K1C) and renin-dependent two-kidney, one-clip (2K1C) renovascular hypertensive rats by radio-immunological measurement of ANF concentration in 18 selected brain areas. Significant changes were found in nine brain areas of 1K1C and in eight brain areas of 2K1C hypertensive rats. Except unidirectional changes in the organum vasculosum laminae terminalis and the supraoptic nucleus, ANF concentration was changed in the opposite direction in all other brain areas, with an activation of the central ANF system in 1K1C and an inhibition in 2K1C hypertension. The localization of the alterations (circumventricular organs, anteroventral third ventricle region, hypothalamo hypophyseal system, brain stem) implies major differences in the central regulation of blood pressure and electrolyte and fluid homeostasis between these two models. The activation of the central ANF system in 1K1C hypertension may be a compensatory mechanism to prevent further increments in blood pressure and plasma volume. In contrast, the depression of the central ANF system in 2K1C hypertension may promote the elevation of the blood pressure.