Abstract 84: Angiotensin II Type 1a Receptor in the Subfornical Organ is Essential for Blood Pressure Regulation and Hydromineral Effects in Mouse Models of Elevated Brain Renin-Angiotensin System Activity.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Aline Hilzendeger ◽  
Deborah R Davis ◽  
Martin D Cassell ◽  
Allyn L Mark ◽  
Justin L Grobe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Intake ◽  
Dna Recombination ◽  
Renin Angiotensin System ◽  
Cre Recombinase ◽  
Subfornical Organ ◽  
Specific Expression ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Conditional Allele

Elevated brain renin-angiotensin system (RAS) activity is necessary to increase blood pressure in many animal models of hypertension. We tested the hypothesis that AT1A receptors (AT1AR) within the subfornical organ (SFO) are required for the phenotypes that result from an increased brain RAS. We examined the effect of SFO-targeted Cre-recombinase mediated ablation of AT1A in mice treated with DOCA-salt (deoxycorticosterone acetate, 50 mg s.c. + ad lib 0.15 M NaCl). Mice homozygous for a conditional allele of the endogenous AT1A gene (AT1ARflox) were administered an adenovirus encoding Cre-recombinase and eGFP (AdCre), or eGFP alone (AdGFP) into the lateral cerebral ventricle, then treated for 3 weeks with DOCA-salt. AdCre reduced DOCA-salt hypertension (AdGFP baseline: 108±3 mmHg; AdGFP pre-DOCA: 104±3; AdGFP post-DOCA: 136±6 vs AdCre baseline: 116±2; Adcre pre-DOCA: 109±3, Adre post-DOCA: 118±5; P≤0.01), polydipsia (AdGFP+DOCA: 20.6±2.1 mL/day; AdCre+DOCA: 11.6±1.1, P<0.05), and sodium intake (AdGFP+DOCA: 2.6±0.3 mEq/day; AdCre+DOCA: 1.8±0.2, P<0.05). AdCre reduced AT1AR mRNA in the SFO (0.4±0.3 fold of AdGFP), without significant effect in the paraventricular or arcuate nuclei, or cortex; this was paralleled by SFO-specific AT1AR genomic DNA recombination. AdCre also caused SFO-specific recombination in ROSA-TdTomato reporter mice. Complementing the DOCA-salt model, we also examined the effect of AT1AR ablation in the SFO of double-transgenic sRA mice. sRA mice exhibit life-long brain-specific angiotensin overproduction via expression of human angiotensinogen via its own promoter and neuron-specific expression of human renin via the synapsin promoter. In sRA mice bred onto the AT1A conditional genetic background, AdCre significantly attenuated the polydipsia (AdGFP: -0.2±2; AdCre: -9.7±2.6 mL/day) and sodium intake (AdGFP: +0.2±0.7; AdCre: -1.3±0.4 mEq/day). Blood pressure measures are in progress. Together, these data highlight the involvement of SFO AT1A receptors in blood pressure in DOCA-salt model and additionally in hydromineral balance in two different models of increased brain RAS activity.

scholarly journals Genetic knockdown of brain-derived neurotrophic factor in the nervous system attenuates angiotensin II-induced hypertension in mice

2019 ◽  
Vol 20 (1) ◽  
pp. 147032031983440 ◽  
Author(s):  
Zhongming Zhang ◽  
Yijing Zhang ◽  
Yan Wang ◽  
Shengchen Ding ◽  
Chenhui Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Nervous System ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Subfornical Organ ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Peripheral Organs ◽  
Induced Hypertension ◽  
Basal Blood Pressure

Introduction: Brain-derived neurotropic factor (BDNF) is expressed throughout the central nervous system and peripheral organs involved in the regulation of blood pressure, but the systemic effects of BDNF in the control of blood pressure are not well elucidated. Materials and methods: We utilized loxP flanked BDNF male mice to cross with nestin-Cre female mice to generate nerve system BDNF knockdown mice, nestin-BDNF (+/–), or injected Cre adenovirus into the subfornical organ to create subfornical organ BDNF knockdown mice. Histochemistry was used to verify injection location. Radiotelemetry was employed to determine baseline blood pressure and pressor response to angiotensin II (1000 ng/kg/min). Real-time polymerase chain reaction was used to measure the expression of renin–angiotensin system components in the laminal terminalis and peripheral organs. Results: Nestin-BDNF (+/–) mice had lower renin–angiotensin system expression in the laminal terminalis and peripheral organs including the gonadal fat pad, and a lower basal blood pressure. They exhibited an attenuated hypertensive response and a weak or similar modification of renin–angiotensin system component expression to angiotensin II infusion. Subfornical organ BDNF knockdown was sufficient for the attenuation of angiotensin II-induced hypertension. Conclusion: Central BDNF, especially subfornical organ BDNF is involved in the maintenance of basal blood pressure and in augmentation of hypertensive response to angiotensin II through systemic regulation of the expression of renin–angiotensin system molecules.

Neurohumoral Response to Hospitalization in Hypertensive Patients

1981 ◽  
Vol 61 (s7) ◽  
pp. 385s-387s ◽  
Author(s):  
P. W. De Leeuw ◽  
G. A. W. Van Soest ◽  
R. Punt ◽  
R. P. L. M. Hoogma ◽  
A. J. P. M. Smout ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Intake ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Group 2 ◽  
Reduced Activity ◽  
Hypotensive Response ◽  
Group 1 ◽  
Noradrenaline Levels

1. To investigate whether reduced activity of pressor systems could explain the spontaneous drop in pressure upon hospitalization, 51 subjects with uncomplicated essential hypertension were admitted to hospital. Sodium intake was fixed at 55 mmol/day. 2. Blood samples for noradrenaline, adrenaline, active renin, angiotensin II and aldosterone were drawn on each morning of the first 3 days of hospitalization; blood pressure was measured at 2 h intervals and values were averaged for each day. 3. Subjects were divided in two groups depending on whether they became normotensive (group 1; n = 12) or remained hypertensive (group 2; n = 39). This distinction was thought to reflect mild and more severe hypertensive groups respectively. 4. Although both groups showed a comparable fall in blood pressure during hospitalization, noradrenaline levels fell more consistently in group 1, whereas adrenaline levels fell only in group 2. The components of the renin—angiotensin—aldosterone system rose, but more conspicuously in group 1. 5. It is concluded that withdrawal of sympathetic activity can only partly explain the hypotensive response to hospitalization. The renin—angiotensin system behaves only passively and appears to be counterproductive to alterations in blood pressure.

scholarly journals Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans

2018 ◽  
Vol 314 (4) ◽  
pp. H796-H804 ◽  
Author(s):  
Silvana G. Cooper ◽  
Darshan P. Trivedi ◽  
Rieko Yamamoto ◽  
Caleb J. Worker ◽  
Cheng-Yuan Feng ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Animal Models ◽  
Systolic Blood Pressure ◽  
Renin Angiotensin System ◽  
Subfornical Organ ◽  
Antihypertensive Drug Therapy ◽  
Angiotensin System ◽  
Human Hypertension ◽  
Renin Angiotensin ◽  
The Brain

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na+ and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.

Rate of activation of renin-angiotensin-aldosterone axis and sodium intake in rats

1989 ◽  
Vol 256 (5) ◽  
pp. H1311-H1315 ◽  
Author(s):  
E. Holtzman ◽  
L. M. Braley ◽  
A. Menachery ◽  
G. H. Williams ◽  
N. K. Hollenberg
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Sodium Intake ◽  
Pressor Response ◽  
Renin Angiotensin System ◽  
Sodium Balance ◽  
Plasma Aldosterone Concentration ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Rate Of Activation

When sodium intake in the rat is reduced abruptly from the typical high level to a very low level (0.02%), sodium excretion falls exponentially, with a half time of 2-3 h. The result is that the rat achieves external sodium balance, in which intake equals excretion, on the new low intake within a few hours. In this study, we assessed the rate of activation of the renin-angiotensin-aldosterone axis and its contribution to blood pressure during that interval. Plasma renin activity and angiotensin II concentration had risen sharply within 8 h and did not change over the next 40 h. Plasma aldosterone concentration, on the other hand, continued to rise over 48 h. Within 8 h, blood pressure dependency on angiotensin II had increased sharply, as assessed by depressor responses to an angiotensin antagonist (Sar1-Ala8-angiotensin II) and to converting-enzyme inhibition (captopril). The depressor response to neither agent changed over the next 40 h. The pressor response to angiotensin II was blunted significantly by 8 h and also did not change over the next 40 h. The findings indicate that the rapid tempo of sodium homeostasis in the rat is matched by an equally rapid tempo of activation of the renin-angiotensin system, although the factors responsible for aldosterone release are probably more complex. Experiments to assess the renin-angiotensin system in the rat must be designed with this rapid tempo in mind.

Terlipressin Versus  Norepinephrine to Correct Refractory Arterial Hypotension after General Anesthesia in Patients Chronically Treated with Renin-Angiotensin System Inhibitors

2003 ◽  
Vol 98 (6) ◽  
pp. 1338-1344 ◽  
Author(s):  
Gilles Boccara ◽  
Alexandre Ouattara ◽  
Gilles Godet ◽  
Eric Dufresne ◽  
Michèle Bertrand ◽  
...  
Keyword(s):  
Blood Pressure ◽  
General Anesthesia ◽  
Arterial Blood Pressure ◽  
Renin Angiotensin System ◽  
Arterial Hypotension ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Arterial Blood ◽  
Long Term Treatment ◽  
Systolic Arterial Blood Pressure

Background Terlipressin, a precursor that is metabolized to lysine-vasopressin, has been proposed as a drug for treatment of intraoperative arterial hypotension refractory to ephedrine in patients who have received long-term treatment with renin-angiotensin system inhibitors. The authors compared the effectiveness of terlipressin and norepinephrine to correct hypotension in these patients. Methods Among 42 patients scheduled for elective carotid endarterectomy, 20 had arterial hypotension following general anesthesia that was refractory to ephedrine. These patients were the basis of the study. After randomization, they received either 1 mg intravenous terlipressin (n = 10) or norepinephrine infusion (n = 10). Beat-by-beat recordings of systolic arterial blood pressure and heart rate were stored on a computer. The intraoperative maximum and minimum values of blood pressure and heart rate, and the time spent with systolic arterial blood pressure below 90 mmHg and above 160 mmHg, were used as indices of hemodynamic stability. Data are expressed as median (95% confidence interval). Results Terlipressin and norepinephrine corrected arterial hypotension in all cases. However, time spent with systolic arterial blood pressure below 90 mmHg was less in the terlipressin group (0 s [0-120 s] vs. 510 s [120-1011 s]; P &lt; 0.001). Nonresponse to treatment (defined as three boluses of terlipressin or three changes in norepinephrine infusion) occurred in zero and eight cases (P &lt; 0.05), respectively. Conclusions In patients who received long-term treatment with renin-angiotensin system inhibitors, intraoperative refractory arterial hypotension was corrected with both terlipressin and norepinephrine. However, terlipressin was more rapidly effective for maintaining normal systolic arterial blood pressure during general anesthesia.

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