Central AT<sub>1</sub> and AT<sub>2</sub> receptors mediate chronic intracerebroventricular angiotensin II‐induced drinking in rats fed high sodium chloride diet from weaning

Camara, Amadou K.S.; Osborn, Jeffrey L.

doi:10.1046/j.1365-201x.2001.00790.x

Cited by 22 publications

(10 citation statements)

References 28 publications

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“…Previous studies have suggested that brain AT2 receptors are important in the regulation of water intake. 51,52 With regard to the cardiovascular effects of ICV Ad-AT 1a -shRNA treatment, there was no evidence of any change in BP or HR. This is also an unpredicted finding based on studies of SFO physiology.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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Abstract-Because of the lack of pharmacological approaches, molecular genetic methods have been required to differentiate between angiotensin type 1(AT 1 ) receptor subtypes AT 1a and AT 1b . RNA interference is a new tool for the study of gene function, producing specific downregulation of protein expression. In this study, we used the small hairpin RNA (shRNA) cassette method to screen target sites for selectively silencing AT 1a or AT 1b receptor subtypes in cultured Neuro-2a cells using real-time RT-PCR. For in vivo functional studies, we used C57BL mice with arterial telemetric probes and computerized licking monitors to test the effect of adenovirus carrying the DNA sequence coding AT 1a shRNA (Ad-AT 1a -shRNA). Ad-AT 1a -shRNA was injected into the lateral ventricle (intracerebroventricular) or the brain stem nucleus tractus solitaries/dorsal vagal nucleus (NTS/DVN) with measurement of water intake, blood pressure (BP), and heart rate (HR) for up to 20 days after injection. Tissue culture studies verified the specificity and the efficiency of the constructs. In animal studies, ␤-galactosidase staining and Ang receptor binding assays showed expression of shRNA and downregulation of Ang AT 1 receptors in the subfornical organ and NTS/DVN by Ͼ70%. Intracerebroventricular injection of Ad-AT 1a -shRNA increased water intake with no effect on BP or HR. In contrast, microinjection of Ad-AT 1a -shRNA into NTS/DVN caused a decrease in BP with no effect on HR or water intake. Results demonstrate the use of the RNA interference method in site-directed silencing of gene expression and provide a method for the in vivo study of Ang AT 1 receptor function. Key Words: blood pressure Ⅲ brain Ⅲ gene regulation Ⅲ renin-angiotensin system B rain angiotensin (Ang) has been implicated in the control of blood pressure (BP), water balance, and hormone secretion. 1-3 Ang type 1 (AT 1 ) receptors are richly expressed in several brain regions, including the subfornical organ (SFO), paraventricular nucleus (PVN), dorsal nucleus vagus (DVN), nucleus tractus solitarii (NTS), and locus coeruleus. 4,5 In rodents, 6 and perhaps in humans, 7,8 there are 2 related AT 1 receptors subtypes, AT 1a and AT 1b . Recent studies by us 4,5 and others 9 demonstrate that AT 1 receptor subtypes AT 1a and AT 1b have similar distribution patterns in the mouse brain. In addition, several lines of reports showed that AT 1a and AT 1b receptor subtypes exhibit individual regulatory functions. 10 -12 Our previous results demonstrated that AT 1a and AT 1b receptors are differentially expressed in response to increased dietary salt and fluid deprivation within mouse brain areas, such as the hypothalamus, anterior pituitary, and brain stem. 4,5,13 However, the precise functional roles of brain AT 1a and AT 1b receptors in specific brain regions remain to be determined.AT 1a and AT 1b receptors share 95% homology in mRNA and amino acid sequences and have similar Ang II binding characteristics. 14 It is difficult to differentiate the subtypes, because there are ...

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Section: Discussionmentioning

confidence: 99%

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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“…Our previous studies suggest the AT 1B subtype of AT 1 receptors may mediate the dipsogenic responses to Ang II (39). Although the drinking response was completely normalized by AT 1 receptor blockade, future experiments will be required to assess the relative contribution of AT 1A and AT 1B receptors or the role, if any, of AT 2 receptors, which have also been implicated in regulating the drinking response to central Ang II (40).…”

Section: Figurementioning

confidence: 99%

Local production of angiotensin II in the subfornical organ causes elevated drinking

Sakai¹,

Agassandian²,

Morimoto³

et al. 2007

J. Clin. Invest.

143

139

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. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II-like immunoreactivity was markedly increased in the subfornical organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGT flox ), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGT flox by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRA flox mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.

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“…Furthermore, AT2 knockout mice have an impaired drinking response to water deprivation (22,31), indicating a role for AT2 receptors in mediating osmotic drinking. Other studies have demonstrated that both AT1 and AT2 blockers inhibit central ANG II-induced water intake (6) and AT2 blockers (PD-123319) inhibit ANG II mediated drinking only in rats, which are fed high-salt diets (10). Thus AT2 receptors may synergistically enhance AT1-mediated water intake only under special circumstances.…”

Section: Discussionmentioning

confidence: 97%

“…Losartan is highly selective for AT1 receptors with 30,000 times more selectivity to AT1 than AT2 receptors (10,11), while PD-123319 is characterized by its high affinity for AT2 receptors with very low affinity for AT1 receptors (50). The dose of the selective AT1 and AT2 blockers were calculated based on rat studies (41,50), after adjustments for the differences in CSF volume between adult rat (ϳ0.3 to 0.4 ml) (34) and near-term fetal sheep (ϳ7 ml) (18).…”

Section: Discussionmentioning

confidence: 99%

Central angiotensin II AT1 receptors mediate fetal swallowing and pressor responses in the near-term ovine fetus

El-Haddad

Ismail

Gayle

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Swallowed volumes in the fetus are greater than adult values (per body weight) and serve to regulate amniotic fluid volume. Central ANG II stimulates swallowing, and nonspecific ANG II receptor antagonists inhibit both spontaneous and ANG II-stimulated swallowing. In the adult rat, AT1 receptors mediate both stimulated drinking and pressor activities, while the role of AT2 receptors is controversial. As fetal brain contains increased ANG II receptors compared with the adult brain, we sought to investigate the role of both AT1 and AT2 receptors in mediating fetal swallowing and pressor activities. Five pregnant ewes with singleton fetuses (130 +/- 1 days) were prepared with fetal vascular and lateral ventricle (LV) catheters and electrocorticogram and esophageal electromyogram electrodes and received three studies over 5 days. On day 1 (ANG II), following a 2-h basal period, 1 ml artificial cerebrospinal fluid (aCSF) was injected in the LV. At time 4 h, ANG II (6.4 microg) was injected in the LV, and the fetus was monitored for a final 2 h. On day 3, AT1 receptor blocker (losartan 0.5 mg) was administered at 2 h, and ANG II plus losartan was administered at 4 h. On day 5, AT2 receptor blocker (PD-123319; 0.8 mg was administered at 2 h and ANG II plus PD-123319 at 4 h. In the ANG II study, LV injection of ANG II significantly increased fetal swallowing (0.9 +/- 0.1 to 1.4 +/- 0.1 swallows/min; P < 0.05). In the losartan study, basal fetal swallowing significantly decreased in response to blockade of AT1 receptors (0.9 +/- 0.1 to 0.4 +/- 0.1 swallows/min; P < 0.05), while central injection of ANG II in the presence of AT1 receptor antagonism did not increase fetal swallowing (0.6 +/- 0.1 swallows/min). In the PD-123319 study, basal fetal swallowing did not change in response to blockade of AT2 receptor (0.9 +/- 0.1 swallows/min), while central injection of ANG II in the presence of AT2 blockade significantly increased fetal swallowing (1.5 +/- 0.1 swallows/min; P < 0.05). ANG II caused significant pressor responses in the control and PD-123319 studies but no pressor response in the presence of AT1 blockade. These data demonstrate that in the near-term ovine fetus, AT1 receptor but not AT2 receptors accessible via CSF contribute to dipsogenic and pressor responses.

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Central AT₁ and AT₂ receptors mediate chronic intracerebroventricular angiotensin II‐induced drinking in rats fed high sodium chloride diet from weaning

Cited by 22 publications

References 28 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Local production of angiotensin II in the subfornical organ causes elevated drinking

Central angiotensin II AT1 receptors mediate fetal swallowing and pressor responses in the near-term ovine fetus

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Central AT1 and AT2 receptors mediate chronic intracerebroventricular angiotensin II‐induced drinking in rats fed high sodium chloride diet from weaning

Cited by 22 publications

References 28 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Local production of angiotensin II in the subfornical organ causes elevated drinking

Central angiotensin II AT1 receptors mediate fetal swallowing and pressor responses in the near-term ovine fetus

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Central AT₁ and AT₂ receptors mediate chronic intracerebroventricular angiotensin II‐induced drinking in rats fed high sodium chloride diet from weaning

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain