Central Renin-angiotensin System Research Articles

Effect of angiotensin II synthesis inhibition on alcohol consumption

Central renin-angiotensin system modulates alcohol intake and inhibition of angiotensin converting enzyme reduces ethanol consumption in rats, and may be potentially useful in the treatment of alcoholism. To study the effect of captopril on alcohol intake, both in humans and animals . In a double-blind, placebo-controlled clinical study, 15 alcoholics who met DSM-IV criteria were randomized to receive captopril 100 mg/day or placebo for 12 weeks. In the experimental study, daily consumption of ethanol (10% v/v), water and solid food was assessed in 12 male Wistar rats before and after the intraperitoneal administration of captopril 50 mg/kg/day. In alcoholics, mean weekly standard alcoholic drink consumption was not different during captopril treatment or placebo. However, both groups had a significantly lower intake than during baseline. Days of abstinence increased and days of drunkeness decreased in the group receiving captopril, when compared with baseline but not with placebo. Craving was significantly reduced by captopril when compared with placebo. In rats, captopril reduced not only alcohol consumption but also water and food intake. Captopril decreases alcohol intake in rats and this effect is not specific for ethanol. Captopril did not alter alcohol consumption in alcoholics when compared with placebo but reduced craving.

Nitric Oxide and Angiotensin II Receptors Mediate the Pressor Effect of Angiotensin II: A Study in Conscious and Zoletil-Anesthetized Rats

The circumventricular structures of the central nervous system and nitric oxide are involved in arterial blood pressure control, and general anesthesia may stimulate the central renin-angiotensin system. We therefore investigated the central role of angiotensin II and nitric oxide on the regulation of systemic arterial blood pressure in conscious and anesthetized rats. Rats with stainless steel cannulae implanted into their lateral ventricle were studied. We injected the AT1 and AT2 angiotensin II receptor antagonists, losartan and PD123319, L-NAME, 7-nitroindazole (nitric oxide synthetase inhibitors), and FK409 (nitric oxide donor agent) into the lateral ventricles. Mean arterial blood pressure (MAP) was recorded in conscious and zoletil-anesthetized rats. Mean +/- sem baseline MAP was 117.5 +/- 2 mm Hg. Angiotensin II injected into the brain lateral ventricle increased MAP from 136.5 +/- 2 mm Hg to 138.5 +/- 4 mm Hg (Delta16 +/- 3 mm Hg to Delta21 +/- 3 mm Hg) for all experimental groups versus control from 116 +/- 2 mm Hg to 120 +/- 3 mm Hg (Delta3 +/- 1 mm Hg to Delta5 +/- 2 mm Hg) (P < 0.05). L-NAME or 7-nitroindazole enhanced the angiotensin II pressor effect (P < 0.05). Prior injection of losartan and PD123319 decreased the angiotensin II pressor effect and the enhancement effect of L-NAME and 7-nitroindazole (P < 0.05). Zoletil anesthesia did not interfere with the effects of angiotensin II, AT1, AT2 antagonists, or nitric oxide synthetase inhibitors. Endogenous nitric oxide functions tonically as a central inhibitory modulator of the angiotensinergic system. AT1 and AT2 receptors influence the angiotensin II central control of arterial blood pressure. Zoletil anesthesia did not interfere with these effects.

Plasticity and impact of the central renin–angiotensin system during development of ethanol dependence

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

Training-Induced Pressure Fall in Spontaneously Hypertensive Rats Is Associated With Reduced Angiotensinogen mRNA Expression Within the Nucleus Tractus Solitarii

Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with (35)S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT(1A)] receptors). Resting arterial pressure and heart rate were higher in SHR(S) (177+/-2 mm Hg, 357+/-12 bpm versus 121+/-1 mm Hg, 320+/-9 bpm in WKY(S); P<0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (-10%) in both groups. Training-induced blood pressure fall (-6.3%) was observed only in SHR(T). In SHR(S) (versus WKY(S)) AT(1A) and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of +67% and +41% for AT(1A) and Aogen, respectively; P<0.05) but unchanged in the gracilis nucleus. Training did not change AT(1A) expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR(T) (P<0.05 versus SHR(S), with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (y=5.95x +41; r=0.55; P<0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure.

Approaches to Establishing Angiotensin II as a Neurotransmitter Revisited

During the past 3 to 4 decades, there has been debate on the presence as well as the role of local tissue renin–angiotensin systems (RAS) in cardiovascular physiology and pathophysiology. Although it is now accepted that all components of the RAS are present in a variety of extrarenal tissues and their regulation may be independent of the circulating hormonal system, the factors contributing to this regulation are still not well understood. Also apparent is that our understanding of the relationships among various cell types expressing individual RAS components and production of specific angiotensin peptides in each tissue is still lacking. This is particularly true of the brain RAS, where even after 20years the question of whether there are angiotensinergic versus reninergic neurons or a complete functioning RAS in cerebrospinal fluid (CSF) or extracellular fluid or glia remains in question.1 Ever since early reports provided biochemical evidence of RAS components in brain, controversy regarding their cellular localization, independence from the circulating system, and authenticity of the proteins and peptides persists. It is well accepted that angiotensinogen is present in CSF/interstitial fluid and localization via immunocytochemistry and in situ hybridization histochemistry reveals that production of the precursor protein is primarily in glia, but also in neurons, within key cardiovascular nuclei. Lingering questions remain concerning local expression of authentic renin in tissues, especially given that prorenin or active renin can be sequestered from the circulation2 and other enzymes can exhibit similar proteolytic profiles under certain conditions. However, there is unequivocal evidence of discrete cells within the pituitary, choroid plexus, medulla oblongata, and hypothalamus that are positive for renin immunoreactivity colocalizing mainly with neurons, but in the medulla oblongata and subfornical organ, in glial elements as well. Evidence of renin mRNA in brain tissue provides a mechanism for local synthesis of the …

Effects of Losartan and Irbesartan administration on brain angiotensinogen mRNA levels

Losartan, 2- n-butyl-4-chloro-5-hydroxymethyl-1-[(2′(1 H-tetrazol-5-yl)-biphenil-4-yl)methyl]imidazole, and Irbesartan, 2- n-butyl-3-[(2′-(1 H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, are two angiotensin AT 1 receptor antagonists largely used in human health care as antihypertensive agents. Their ability to cross the blood–brain barrier and to influence the central renin–angiotensin system are widely investigated, but how this brain system responds to the subchronic and chronic block of the angiotensin AT 1 receptor is still unknown. Normotensive rats were intragastrically implanted for 7- and 30-day administration, with a dose of 3 and 30 mg/kg body weight. Treatments were shown to influence, in a dose-, time- and brain-area-dependent manner, angiotensinogen mRNA levels in scanned areas. This study showed a general up-regulation of angiotensinogen mRNA expression after 7 days and a widespread down-regulation or basal level of expression after a 30-day administration of two angiotensin AT 1 receptor antagonists.

Central angiotensin II controls alcohol consumption via its AT1 receptor

Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system [TGR(ASrAOGEN)680]. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.

Central angiotensin II-induced pressor responses and neural activity in utero and hypothalamic angiotensin receptors in preterm ovine fetus.

The central renin-angiotensin system is important in the control of blood pressure in the adult. However, few data exist about the in utero development of central angiotensin-mediated pressor responses. Our recent studies have shown that the application of ANG II into the fetal brain can increase blood pressure at near term. The present study determined fetal blood pressure and heart rate in response to a central application of ANG II in the chronically prepared preterm ovine fetus, determined the action sites marked by c-Fos expression in the fetal central pathways after intracerebroventricular injection of ANG II in utero, and determined angiotensin subtype 1 receptors in the fetal hypothalamus. Central injection of ANG II significantly increased fetal mean arterial pressure (MAP). Adjusted fetal MAP against amniotic pressure was also increased by ANG II. Fetal heart rate was subsequently decreased after the central administration of ANG II and/or the increase of blood pressure. ANG II induced c-Fos expression in the central putative cardiovascular area, the paraventricular nuclei in the brain sympathetic pathway. Application of ANG II also caused intense Fos immunoreactivity in the tractus solitarius nuclei in the hindbrain. In addition, intense angiotensin subtype 1 receptors were expressed in the hypothalamus at preterm. These data demonstrate that central ANG II-related pressor centers start to function as early as at preterm and suggest that the central angiotensin-related sympathetic pathway is likely intact in the control of blood pressure in utero.

Récepteurs de l’angiotensine dans le cerveau et adaptation au stress

In this short review, we hypothesize that the central renin-angiotensin system might participate to the initiation of compensatory responses to a stressor agent. Regulation of the expression of the brain angiotensin receptors might constitute a primary molecular mechanism by which this protecting action would take place. We illustrate this possibility by investigating the expression of the angiotensin type 1 receptor in the hypothalamus in response to systemic and neurogenic stressors.

In utero development of central ANG-stimulated pressor response and hypothalamic fos expression

Central renin–angiotensin system (RAS) is as important as the peripheral RAS in the control of the cardiovascular homeostasis in the adult. However, previous fetal studies on angiotensin II (ANG II)-induced cardiovascular responses focused exclusively on the peripheral side. Thus, few data exist characterizing the in utero development of central angiotensin-mediated pressor responses. The present study determined cardiovascular responses to central application of ANG II in the chronically prepared near-term ovine fetus, and determined the action sites marked by c-fos expression in the fetal hypothalamus following intracerebroventricular (icv) injection of ANG II in utero. ANG II significantly increased fetal systolic, diastolic, and mean arterial pressure (MAP) within 5 min after injection of this peptide into the brain. Adjusted fetal MAP against amniotic pressure was also increased by icv ANG II, associated with increased c-fos in the central putative cardiovascular area—the paraventricular nuclei (PVN). Application of ANG II also induced intense c-fos expression in the supraoptic nuclei (SON), accompanied by a significant increase of fetal plasma vasopressin (AVP) levels, while maternal blood pressure (BP) and plasma AVP concentration were not changed. These results indicate that the central ANG II-mediated pressor response is functional at the last third of gestation, acting at the sites consistent with the cardiovascular neural network in the hypothalamus.

Angiotensin receptor-like immunoreactivity in adult brain white matter astrocytes and oligodendrocytes.

Most of the physiological effects of brain angiotensins are currently believed to be mediated by angiotensin receptors located principally on neurons. However, numerous studies in vitro have demonstrated the presence of functional angiotensin receptors on brain astrocytes, raising the possibility that glial cells may also participate in mediating the effects of the central renin-angiotensin system. Nevertheless, it is uncertain whether these cells in situ express angiotensin receptors, raising questions about the physiological significance of results observed in cell cultures. We have examined the distribution of angiotensin receptor-like immunoreactivity in glial cells in white matter tracts in the adult CNS, using a panel of antisera to the AT1 and AT2 angiotensin receptors. Antiserum preadsorption and/or Western blot demonstrated the specificity of the antisera in brain tissue. In immunohistochemical experiments, the AT1 antisera selectively labeled AT1-expressing neurons in the piriform cortex, whereas the AT2 antiserum stained cells in the trigeminal motor nucleus, these being nuclei known to express AT1 and AT2 receptors, respectively. Using double-label immunohistochemistry, we observed AT1- and AT2-immunoreactive astrocytes and oligodendrocytes in white matter tracts, which include the rat cerebellar white matter, periventricular white matter, and optic nerve, in addition to the bovine corpus callosum and human subcortical white matter. In contrast, astrocytes in the gray matter region of the cerebral cortex were not found to be angiotensin receptor-like immunoreactive. These results demonstrate the presence of AT1 and/or AT2 angiotensin receptor-like immunoreactivity in brain white matter macroglial cells in situ and support the idea that glial cells may play a more important role in the central renin-angiotensin system than previously thought.

Central injection of captopril inhibits the blood pressure response to intracerebroventricular choline

In the present study, we investigated the involvement of the brain renin-angiotensin system in the effects of central cholinergic stimulation on blood pressure in conscious, freely moving normotensive rats. In the first step, we determined the effects of intracerebroventricular (icv) choline (50, 100 and 150 microg) on blood pressure. Choline increased blood pressure in a dose-dependent manner. In order to investigate the effects of brain renin-angiotensin system blockade on blood pressure increase induced by choline (150 microg, icv), an angiotensin-converting enzyme inhibitor, captopril (25 and 50 microg, icv), was administered 3 min before choline. Twenty-five microg captopril did not block the pressor effect of choline, while 50 microg captopril blocked it significantly. Our results suggest that the central renin-angiotensin system may participate in the increase in blood pressure induced by icv choline in normotensive rats.

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 AT1receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT1receptor 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 AT1receptor 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 with125I- (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 mgkg−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 ± 116dpmmm−2 of CTRL;P< 0.05). Furthermore, eprosartan inhibited angiotensin II receptor binding in discrete brain areas, which express exclusively, or predominantly, AT1receptors both outside and within the blood–brain barrier, such as the paraventricular nucleus ( 180 ± 47 and 130 ± 18 vs 545 ± 99 dpmmm−2of CTRL;P< 0.05), the subfornical organ ( 106 ± 26 and 112 ± 17 vs 619 ± 256 dpmmm−2of CTRL;P< 0.05), and the organum vasculosum laminae terminalis ( 461 ± 110 and 763 ± 136 vs 1033 ± 123dpmmm−2 of CTRL;P< 0.05). These results emphasize that eprosartan readily crosses the blood–brain barrier in vivo and selectively inhibits binding to AT1receptors in specific brain nuclei. The modulation of central regulatory mechanisms might contribute to AT1receptor antagonists overall therapeutic efficacy in cardiovascular disease.

Alterations of the renin-angiotensin system at the RVLM of transgenic rats with low brain angiotensinogen.

The transgenic rats TGR(ASrAOGEN) (TGR) with low levels of brain angiotensinogen were analyzed for cardiovascular reactivity to microinjections of ANG II and angiotensin receptor (AT(1)) antagonists [CV-11974, AT(1) specific; A-779, ANG-(1--7) selective; sarthran, nonspecific] into the rostral ventrolateral medulla (RVLM) of conscious rats. Microinjection of ANG II resulted in a significantly higher increase in the mean arterial pressure (MAP) of TGR than control [Sprague-Dawley (SD)] rats, suggesting an upregulation of ANG II receptors in TGR. CV-11974 produced an increase in MAP of SD but not in TGR rats. A-779 produced a depressor response in SD but not in TGR rats. Conversely, sarthran produced a similar decrease of MAP in both rat groups. The pressor effect of the AT(1) antagonist may indicate an inhibitory role of AT(1) receptors in the RVLM. On the other hand, ANG-(1--7) appears to have a tonic excitatory role in this region. The altered response to specific angiotensin antagonists in TGR further supports the functionally relevant decrease in angiotensins in the brains of TGR and corroborates the importance of the central renin-angiotensin system in cardiovascular homeostasis.

In vivo effects of partial phosphorothioated at, receptor antisense oligonucleotides in spontaneously hypertensive and normotensive rats

Partial phosphorothioate (PS) antisense oligodeoxynucleotides (ODNs) targeted against rat AT1 receptor mRNA have been used to control blood pressure in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Molecules were injected intracerebroventricularly (i.c.v., right lateral ventricle) in freely moving animals. The antisense ODN lowered the mean arterial pressure (MAP) 24 hours (-43 mmHg+/-10) and 48 hours (-30 mmHg+/-13) after injection, while the control ODN molecule had no significant effects. The observed decrease of blood pressure was due to a specific inhibition of AT1 receptor gene expression, since the level of its mRNA, monitored by reverse transcription (RT)- polymerase chain reaction (PCR), was significantly reduced by antisense molecule (-40%), compared to sense one. In normotensive rats no effect on MAP have been observed, while AT1 receptor gene expression is reduced (-40%) by antisense treatment. It is known that SHRs have an enhanced basal activity of the central renin-angiotensin system that induces an increase in central sympathetic outflow. Instead in WKY rats the central sympathetic outflow is not conditioned by the enhanced activity of brain renin-angiotensin system. Therefore in normotensive rats although partial PS ODN reduces the AT1 mRNA level this will not result in a modification of the sympathetic outflow and no change in MAP level would be observed.

Increased brain angiotensin receptor in rats with chronic high-output heart failure

The renin-angiotensin system (RAS) plays a key role in the pathophysiology of chronic heart failure (CHF). In rats, we reported that CHF enhances dipsogenic responses to centrally administered angiotensin I, and central inhibition of the angiotensin-converting enzyme (ACE) prevents cardiac hypertrophy in CHF. This suggests that the brain RAS is activated in CHF. To clarify the mechanism of the central RAS activation in CHF, we examined brain ACE and the angiotensin receptor (AT) among rats with CHF. We created high-output heart failure in 22 male Sprague-Dawley rats by aortocaval shunt. Four weeks after surgery, we examined ACE mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and AT by binding autoradiography. ACE mRNA levels were not significantly increased in the subfornical organ (SFO), the hypothalamus, or in the lower brainstem of CHF rats (n = 5) compared with sham-operated rats (SHM) (n = 6). Binding densities for type 1 AT (AT1) in the SFO (P < .05), paraventricular hypothalamic nuclei (P < .05), and solitary tract nuclei (P < .05) were higher in rats with CHF (n = 5) than in SHM rats (n = 6). Thus, in rats with CHF, AT1 expression is increased in brain regions that are closely related to water intake, vasopressin release, and hemodynamic regulation. The fact that AT1 expression was upregulated in important brain regions related to body fluid control in CHF rats indicates that the brain is a major site of RAS action in CHF rats and, therefore, a possible target site of ACE-inhibitors in the treatment of CHF.

Estrogen decreases hypothalamic angiotensin II AT 1 receptor binding and mRNA in the female rat

Estrogen has been shown to modulate angiotensin II (AngII)-regulated behaviors, such as thirst, and may do so by influencing the central renin–angiotensin system (RAS). While numerous studies have attempted to correlate changes in AngII receptors or other components of the RAS with estrogen treatment, the low abundance of these genes has made comparisons difficult. Generally, such experiments have relied on traditional approaches to analyze gene expression that often restrict the experimenter to studying only a few mRNA species, whereas a behavior as complex as thirst may be influenced by changes in multiple genes. The present experiments utilized quantitative receptor autoradiography and mRNA expression profiling to identify and compare AngII receptors and their mRNA levels as well as other components of the RAS in female rat pituitary and hypothalamic–thalamic–septal (HTS) tissue samples. This relatively new approach to the study of gene expression permits the simultaneous comparison of multiple genes from a single tissue sample. These studies revealed that ovariectomized (OVX) female rats treated with estradiol benzoate (EB) had a 30%–40% reduction in the levels of AT 1 receptor mRNA in pituitary and HTS samples as compared to OVX, control animals. In the pituitary, the mRNA levels for angiotensinogen (AGT) were increased by 45% following estrogen administration. In addition, a reduction in [ 125 I ]-AngII binding to AT 1 receptors in the pituitary and the subfornical organ was measured following estrogen treatment. These results suggest that estrogen may modulate the pituitary and central RAS through a coordinate regulation of the angiotensin receptors and the levels of newly synthesized AngII.

Central renin–angiotensin system in stress adaptation

Central renin–angiotensin system in stress adaptation

Functional evidence for subfornical organ-intrinsic conversion of angiotensin I to angiotensin II.

Using extracellular electrophysiological recording in an in vitro slice preparation, we investigated whether ANG I can be locally converted to the functionally active ANG II within the rat subfornical organ (SFO). ANG I and ANG II (10(-8)-10(-7) M) excited approximately 75% of all neurons tested with both peptides (n = 25); the remainder were insensitive. The increase in firing rate and the duration and the latency of the responses of identical neurons, superfused with equimolar concentrations of ANG I and ANG II, were not different. The threshold concentrations of the ANG I- and ANG II-induced excitations were both 10(-9) M. Inhibition of the angiotensin-converting enzyme by captopril (10(-4) M; n = 8) completely blocked the ANG I-induced excitation, a 10-fold lower dose was only effective in two of four neurons. The AT1-receptor antagonist losartan (10(-5) M; n = 6) abolished the excitation caused by ANG I and ANG II. Subcutaneous injections of equimolar doses of ANG I and ANG II (200 microliters; 2 x 10(-4) M) in water-sated rats similarly increased water intake by 2.4 +/- 0.5 (n = 16) and 2. 7 +/- 0.4 ml (n = 20) after 1 h, respectively. Control rats receiving saline drank 0.07 +/- 0.06 ml under these conditions. Pretreatment with a low dose of captopril (2.3 x 10(-3) M) 10 min before the injection of ANG I caused a water intake of 2.8 +/- 0.5 ml (n = 10), whereas a high dose of captopril (4.6 x 10(-1) M) suppressed the dipsogenic response of ANG I entirely (n = 11). These data provide direct functional evidence for an SFO-intrinsic renin-angiotensin system (RAS) and underline the importance of the SFO as a central nervous interface connecting the peripheral with the central RAS.

Central vasopressin is modulated by chronic blockade of the renin-angiotensin system in experimental left ventricular hypertrophy

We studied the interaction of the central renin-angiotensin system (RAS) and vasopressin system in rats with left ventricular hypertrophy (LVH) due to aortic banding. In these animals plasma vasopressin is elevated and vasopressin content is increased in specific brain areas. Chronic blockade of the RAS by angiotensin-converting enzyme (ACE) inhibition (ramipril) and AT 1 receptor antagonism (losartan) significantly attenuated circulating and central vasopressin in rats with LVH. Given the antidiuretic, vasoconstrictive, and growth-promoting effects, vasopressin may participate in the cardiovascular alterations in LVH. Blockade of the RAS strongly ameliorates central and peripheral vasopressin. Therefore, central modulatory effects on vasopressin might contribute to the therapeutic efficacy of ACE inhibitors and AT 1 antagonists.