AT1 receptors in the subfornical organ modulate arterial pressure and the baroreflex in two-kidney, one-clip hypertensive rats

The subfornical organ (SFO), a forebrain circumventricular organ that lies outside the blood-brain barrier, has been implicated in arterial pressure and baroreflex responses to angiotensin II (ANG II). We tested whether pharmacological inhibition or selective silencing of SFO ANG II type 1 receptors (AT1R) of two-kidney, one-clip rats with elevated plasma ANG II decreases resting arterial pressure and renal sympathetic nerve activity (RSNA) and/or modulates arterial baroreflex responses of heart rate (HR) and RSNA. Male Sprague-Dawley rats underwent renal artery clipping [2-kidney, 1-clip (2K,1C)] or sham clipping (sham). After 6 wk, conscious rats instrumented with vascular catheters, renal nerve electrodes, and a cannula directed to the SFO were studied. In another set of experiments, rats were instrumented with hemodynamic and nerve radio transmitters and injected with scrambled RNA or silencing RNA targeted against AT1R. Mean arterial pressure (MAP) was significantly higher in 2K,1C rats. Acute SFO injection with the AT1R inhibitor losartan did not change MAP in sham or 2K,1C rats. Baroreflex curves of HR and RSNA were shifted rightward in 2K,1C rats. Losartan exerted no effect. SFO AT1R knockdown did not influence MAP in sham rats but decreased MAP in 2K,1C rats, despite no change in plasma ANG II or resting RSNA. AT1R knockdown prevented the reduction in maximum gain and slope of baroreflex responses of HR and RSNA; the reduced RSNA response to baroreceptor unloading was partially restored in 2K,1C rats. These findings show that AT1R activation within the SFO contributes to hypertension and baroreflex dysfunction in 2K,1C rats and highlight the temporal requirement for reversal of these effects.

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Glucocorticoids potentiate central actions of angiotensin to increase arterial pressure

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.6.r1719 ◽

2001 ◽

Vol 280 (6) ◽

pp. R1719-R1726 ◽

Cited By ~ 26

Author(s):

Deborah A. Scheuer ◽

Andrea G. Bechtold

Keyword(s):

Heart Rate ◽

Arterial Pressure ◽

Pressor Response ◽

Ang Ii ◽

Sprague Dawley ◽

Guide Cannula ◽

Intravenous Injections ◽

Sprague Dawley Rats ◽

And Control

Experiments were performed to determine if glucocorticoids potentiate central hypertensive actions of ANG II. Male Sprague-Dawley rats were treated for 3 days to 3 wk with corticosterone (Cort). Experiments were performed in conscious rats that had previously been instrumented with arterial and venous catheters and an intracerebroventricular guide cannula in a lateral ventricle. Baseline arterial pressure (AP) was greater in Cort-treated rats than in control rats (119 ± 2 vs. 107 ± 1 mmHg, P < 0.01). Microinjection of ANG II intracerebroventricularly produced a significantly larger increase in AP in Cort-treated rats than in control rats. For example, at 30 ng ANG II, AP increased by 23 ± 1 and 16 ± 2 mmHg in Cort-treated and control rats, respectively ( P < 0.01). Microinjection of an angiotensin type 1 receptor antagonist significantly decreased AP (−6 ± 2 mmHg) and heart rate (−26 ± 7 beats/min) in Cort-treated but not control rats. Increases in AP produced by intravenous administration of ANG II were not different between control and Cort-treated rats. Intravenous injections of ANG II antagonist had no significant effects on mean AP or heart rate in control or Cort-treated rats. Therefore, a sustained increase in plasma Cort augments the central pressor effects of ANG II without altering the pressor response to peripheral administration of the hormone.

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Raspberry Consumption Attenuates Angiotensin II-Induced Oxidative Stress in the Subfornical Organ in Male Sprague-Dawley Rats

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_008 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 298-298

Author(s):

Jasmynne Blacks ◽

Ferdinand Althammer ◽

Rami Najjar ◽

Maureen Meister ◽

Jessica Dahn ◽

...

Keyword(s):

Oxidative Stress ◽

Subfornical Organ ◽

Saline Control ◽

Ang Ii ◽

Sprague Dawley ◽

Funding Sources ◽

Food Research ◽

Food And Agriculture ◽

Sprague Dawley Rats ◽

Freeze Dried

Abstract Objectives To examine whether raspberry (RB) attenuates oxidative stress induced by angiotensin (Ang) II in the subfornical organ (SFO) of the brain in rats. Methods Male Sprague-Dawley rats were fed an AIN-93M diet with or without 10% w/w freeze-dried RB powder for seven weeks. At week 4, rats were implanted with subcutaneous osmotic minipumps that delivered 0.9% saline (Control) or Ang II (270 ng/kg body weight/day) for another three weeks. Brain region-specific tissue punches were collected from flash-frozen sections containing the SFO. NADPH oxidase (NOX) 2 and 4 and superoxide dismutase (SOD) 1 and 2 were measured in SFO using western blot. Results were analyzed using one-way ANOVA followed by Tukey post hoc test. Data were normalized to control and are expressed as means ± standard deviation. Results Ang II significantly increased NOX2 expression compared to control (1.24 ± 0.1, n = 5, vs 1.00 ± 0.07-fold, n = 3, P = 0.009) while RB supplementation significantly attenuated Ang II-induced increases in NOX2 (0.91 ± 0.05-fold, n = 4; P = 0.0006). Ang II also increased NOX4 expression compared to control (2.11 ± 1.2, n = 9, vs 0.98 ± 0.4-fold, n = 6, P = 0.04), but RB supplementation did not significantly attenuate this effect (1.30 ± 0.36-fold, n = 10, P = 0.11). RB increased expression of SOD1 (1.52 ± 0.20-fold, n = 4) compared to control (1.00 ± 0.15-fold, n = 3, P = 0.009) and Ang II alone (1.08 ± 0.16-fold, n = 5, P = 0.01). On the other hand, Ang II treatment decreased SOD2 expression compared to control (0.62 ± 0.05, n = 5, vs 1.00 ± 0.09-fold, n = 3, P = 0.0001), but the RB supplementation did not prevent this effect (0.72 ± 0.07-fold, n = 4, P = 0.16). Conclusions Our findings suggest that RB supplementation decreases Ang II-induced oxidative stress in the SFO by decreasing NOX2 and increasing SOD1 expression. Future investigations are warranted to elucidate the effects of RB on oxidative stress pathways in the SFO. Funding Sources This work was supported by the Agriculture and Food Research Initiative (grant no. 2019–67,017-29,257/project accession no. 1,018,642) from the USDA National Institute of Food and Agriculture.

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Subfornical organ and cardiovascular influences on identified septal neurons

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1988.254.3.r544 ◽

1988 ◽

Vol 254 (3) ◽

pp. R544-R551 ◽

Cited By ~ 1

Author(s):

S. D. Donevan ◽

A. V. Ferguson

Keyword(s):

Blood Pressure ◽

Medial Septum ◽

Subfornical Organ ◽

Ang Ii ◽

Sprague Dawley ◽

Diagonal Band ◽

Sprague Dawley Rats ◽

Relay Neuron ◽

Afferent Information ◽

Septal Neurons

We have identified, in urethan-anesthetized male Sprague-Dawley rats, a polysynaptic pathway connecting the subfornical organ (SFO) with the paraventricular nucleus (PVN) with a relay neuron in the medial septum-diagonal band of Broca (MS-DBB). Extracellular recordings were obtained from 136 MS-DBB neurons antidromically identified as projecting to the PVN. SFO stimulation orthodromically activated 79% of these cells (mean latency, 21.2 +/- 0.6 ms; mean duration, 6.0 +/- 0.2 ms), whereas stimulation in the fornix or hippocampal commissure had no effect. Of 35 identified MS-DBB neurons tested with systemic angiotensin II (ANG II), eight showed increases and six decreases in excitability that coincided with the ANG II-induced increase in blood pressure. To determine whether such changes were blood pressure related, 23 of the 35 identified MS-DBB neurons tested with ANG II were tested with systemic epinephrine. In every case the effect of epinephrine was similar to that of ANG II. These findings suggest that neurons in the MS-DBB receive afferent information from the SFO and the cardiovascular system. These cells in turn may activate neurons involved in the control of a variety of autonomic functions.

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Glucocorticoids reduce responses to AMPA receptor activation and blockade in nucleus tractus solitarius

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01033.2002 ◽

2003 ◽

Vol 284 (5) ◽

pp. H1751-H1761 ◽

Cited By ~ 9

Author(s):

Sylvan S. Shank ◽

Deborah A. Scheuer

Keyword(s):

Arterial Pressure ◽

Ampa Receptors ◽

Sympathetic Nerve Activity ◽

Nucleus Tractus Solitarius ◽

Receptor Activation ◽

Sprague Dawley ◽

Nerve Activity ◽

Renal Sympathetic Nerve Activity ◽

Sprague Dawley Rats ◽

Renal Sympathetic

We tested the hypothesis that glucocorticoids attenuate changes in arterial pressure and renal sympathetic nerve activity (RSNA) in response to activation and blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors within the nucleus of the solitary tract (NTS). Experiments were performed in Inactin-anesthetized male Sprague-Dawley rats treated for 7 ± 1 days with a subcutaneous corticosterone (Cort) pellet or in control rats. Baseline mean arterial pressure (MAP) was significantly higher in Cort-treated rats (109 ± 2 mmHg, n = 39) than in control rats (101 ± 1 mmHg, n = 48, P < 0.05). In control rats, microinjection of AMPA (0.03, 0.1, and 0.3 pmol/100 nl) into the NTS significantly decreased MAP at all doses and decreased RSNA at 0.1 and 0.3 pmol/100 nl. Responses to AMPA in Cort-treated rats were attenuated at all doses of AMPA ( P < 0.05). Responses to the AMPA-kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were also significantly reduced in Cort-treated rats relative to control rats. Blockade of glucocorticoid type II receptors with mifepristone significantly enhanced responses to CNQX in both control and Cort rats. We conclude that glucocorticoids attenuate MAP and RSNA responses to activation and blockade of AMPA receptors in the NTS.

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Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00331.2015 ◽

2016 ◽

Vol 310 (2) ◽

pp. R197-R208 ◽

Cited By ~ 8

Author(s):

Noreen F. Rossi ◽

Russell Pajewski ◽

Haiping Chen ◽

Peter J. Littrup ◽

Maria Maliszewska-Scislo

Keyword(s):

Renal Artery ◽

Renal Denervation ◽

Renal Tissue ◽

Reflex Response ◽

Ang Ii ◽

Neural Responses ◽

Sprague Dawley ◽

Renal Nerve ◽

Contralateral Kidney ◽

Sprague Dawley Rats

Renal artery stenosis is increasing in prevalence. Angioplasty plus stenting has not proven to be better than medical management. There has been a reluctance to use available denervation methodologies in this condition. We studied conscious, chronically instrumented, two-kidney, one-clip (2K-1C) Goldblatt rats, a model of renovascular hypertension, to test the hypothesis that renal denervation by cryoablation (cryo-DNX) of the renal nerve to the clipped kidney decreases mean arterial pressure (MAP), plasma and tissue ANG II, and contralateral renal sympathetic nerve activity (RSNA). Five-week-old male Sprague-Dawley rats underwent sham (ShC) or right renal artery clipping (2K-1C), placement of telemetry transmitters, and pair-feeding with a 0.4% NaCl diet. After 6 wk, rats were randomly assigned to cryo-DNX or sham cryotreatment (sham DNX) of the renal nerve to the clipped kidney. MAP was elevated in 2K-1C and decreased significantly in both ShC cryo-DNX and 2K-1C cryo-DNX. Tissue norepinephrine was ∼85% lower in cryo-DNX kidneys. Plasma ANG II was higher in 2K-1C sham DNX but not in 2K-1C cryo-DNX vs ShC. Renal tissue ANG II in the clipped kidney decreased after cryo-DNX. Baseline integrated RSNA of the unclipped kidney was threefold higher in 2K-1C versus ShC and decreased in 2K-1C cryo-DNX to values similar to ShC. Maximum reflex response of RSNA to baroreceptor unloading in 2K-1C was lower after cryo-DNX. Thus, denervation by cryoablation of the renal nerve to the clipped kidney decreases not only MAP but also plasma and renal tissue ANG II levels and RSNA to the contralateral kidney in conscious, freely moving 2K-1C rats.

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Endogenous angiotensin II inhibits natriuresis after acute volume expansion in the neonatal rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.2.r393 ◽

1996 ◽

Vol 270 (2) ◽

pp. R393-R397 ◽

Cited By ~ 7

Author(s):

R. L. Chevalier ◽

B. A. Thornhill ◽

D. C. Belmonte ◽

A. J. Baertschi

Keyword(s):

Volume Expansion ◽

Saline Group ◽

At1 Receptor ◽

Neonatal Rat ◽

Ang Ii ◽

Sprague Dawley ◽

Plasma Aldosterone Concentration ◽

Arterial Blood ◽

Sprague Dawley Rats

Compared with the adult, the neonatal renal natriuretic response to acute volume expansion (VE) is attenuated. To test the hypothesis that antinatriuresis is mediated by endogenous angiotensin I (ANG II), Sprague-Dawley rats were given losartan, an ANG II type 1 (AT1)-receptor inhibitor (40 mg.kg-1.day-1) from birth to 14-17 days. Control littermates received saline vehicle. Anesthetized rats underwent acute saline VE for measurement of mean arterial blood pressure (MAP), plasma aldosterone concentration (Paldo), plasma atrial natriuretic peptide (PANP), glomerular filtration rate (GFR), sodium excretion (UNaV), potassium excretion (UKV), and urine guanosine 3',5'-cyclic monophosphate excretion (UcGMPV). Losartan increased basal urine flow fivefold, UNaV 10-fold, and UKV twofold. Acute VE induced marked diuresis, natriuresis, and kaliuresis in the losartan but not in the saline group. This occurred without change in Paldo and PANP and despite lower MAP, GFR, and UcGMPV. In addition, losartan did not affect release of cGMP from isolated glomeruli stimulated by ANP or sodium nitroprusside. We conclude that the limited renal response to acute VE in the neonate results from stimulation of tubular Na reabsorption by ANG II acting on the AT1 receptor.

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Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.5.r1388 ◽

2001 ◽

Vol 280 (5) ◽

pp. R1388-R1392 ◽

Cited By ~ 57

Author(s):

Barbara T. Alexander ◽

Kathy L. Cockrell ◽

A. Nicole Rinewalt ◽

Jason N. Herrington ◽

Joey P. Granger

Keyword(s):

Arterial Pressure ◽

Receptor Antagonist ◽

Jugular Vein ◽

Ang Ii ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Endothelin System ◽

Pressure Changes ◽

Renal Expression

The purpose of this study was to determine the role of endothelin in mediating the renal hemodynamic and arterial pressure changes observed during chronic ANG II-induced hypertension. ANG II (50 ng · kg−1 · min−1) was chronically infused into the jugular vein by miniosmotic pump for 2 wk in male Sprague-Dawley rats with and without endothelin type A (ETA)-receptor antagonist ABT-627 (5 mg · kg−1 · day−1) pretreatment. Arterial pressure increased in ANG II rats compared with control rats (149 ± 5 vs. 121 ± 6 mmHg, P< 0.05, respectively). Renal expression of preproendothelin mRNA was increased by ∼50% in both the medulla and cortex of ANG II rats. The hypertensive effect of ANG II was completely abolished in rats pretreated with the ETA-receptor antagonist (114 ± 5 mmHg, P < 0.05). Glomerular filtration rate was decreased by 33% in ANG II rats, and this response was attenuated in rats pretreated with ETA-receptor antagonist. These data indicate that activation of the renal endothelin system by ANG II may play an important role in mediating chronic renal and hypertensive actions of ANG II.

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Down-regulation of Brain Gα12 attenuates Angiotensin II Dependent Hypertension

American Journal of Hypertension ◽

10.1093/ajh/hpz176 ◽

2019 ◽

Author(s):

Juan Gao ◽

Ian Denys ◽

Amir Shahien ◽

Jane Sutphen ◽

Daniel R Kapusta

Keyword(s):

Angiotensin Ii ◽

Baroreflex Sensitivity ◽

Pressor Response ◽

Ang Ii ◽

Protein Signaling ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Induced Hypertension ◽

Chronic Infusion

Abstract Background Angiotensin II (Ang II) activates central Angiotensin II type 1 receptors (AT1R) to increase blood pressure (BP) via multiple pathways. However, whether central Gα proteins contribute to Ang II induced hypertension remains unknown. We hypothesized that AT1R couple with Gα12 and/or Gαq to produce sympatho-excitation and increase BP and downregulation of these Gα subunit proteins will attenuate Ang II dependent hypertension. Methods & Results After chronic infusion of Ang II (s.c. 350 ng/kg/min) or vehicle for 2-weeks, Ang II evoked an increase in Gα12 expression, but not Gαq in the RVLM of Sprague-Dawley rats. In other studies, rats that received Ang II or vehicle infusion s.c. were simultaneously infused i.c.v. with a scrambled (SCR) or Gα12 oligodeoxynucleotide (ODN; 50 μg/day). Central Gα12 ODN infusion lowered mean BP in Ang II infused rats compared with SCR ODN infusion (14- day peak; 133 ± 12 vs 176 ± 11 mmHg). Compared to the SCR ODN group, Ang II infused rats that received i.c.v. Gα12 ODN showed a greater increase in heart rate to atropine, an attenuated reduction in BP to chlorisondamine, and an improved baroreflex sensitivity. In addition, central Gα12 and Gαq ODN pretreatment blunted the pressor response to an acute i.c.v. injection of Ang II (i.c.v., 200 ng). Conclusions These findings suggest that central Gα12 protein signaling pathways play an important role in the development of chronic AngII-dependent hypertension in rats.

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Contribution of the subfornical organ to angiotensin II-induced hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00823.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. H680-H685 ◽

Cited By ~ 55

Author(s):

Michael D. Hendel ◽

John P. Collister

Keyword(s):

Angiotensin Ii ◽

Chronic Phase ◽

Circumventricular Organs ◽

Subfornical Organ ◽

Saline Control ◽

Sham Operation ◽

Ang Ii ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Induced Hypertension

Previous studies clearly demonstrated acute actions of angiotensin II (ANG II) at one of the central circumventricular organs, the subfornical organ (SFO), but studies demonstrating a role for the SFO in the chronic actions of ANG II remain uncertain. The purpose of this study was to examine the role of the SFO in the chronic hypertensive phase of ANG II-induced hypertension. We hypothesized that the SFO is necessary for the full hypertensive response observed during the chronic phase of ANG II-induced hypertension. To test this hypothesis, male Sprague-Dawley rats were subjected to sham operation (sham rats) or electrolytic lesion of the SFO (SFOx rats). After 1 wk, the rats were instrumented with venous catheters and radiotelemetric transducers for intravenous administration of ANG II and measurement of blood pressure and heart rate, respectively. Rats were then allowed 1 wk for recovery. After 3 days of saline control infusion (7 ml of 0.9% NaCl/day), sham and SFOx rats were infused with ANG II at 10 ng·kg−1·min−1 iv for 10 consecutive days and then allowed to recover for 3 days. A 0.4% NaCl diet and distilled water were provided ad libitum. At day 5 of ANG II infusion, mean arterial pressure increased 11.7 ± 3.0 mmHg in sham rats ( n = 9) but increased only 3.7 ± 1.4 mmHg in SFOx rats ( n = 9). This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the SFO is necessary for the full hypertensive response to chronic ANG II administration.

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Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

AJP Renal Physiology ◽

10.1152/ajprenal.00252.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. F861-F867 ◽

Cited By ~ 17

Author(s):

Melvin R. Hayden ◽

Nazif A. Chowdhury ◽

Shawna A. Cooper ◽

Adam Whaley-Connell ◽

Javad Habibi ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Systolic Blood Pressure ◽

Proximal Tubule ◽

Structural Damage ◽

Kidney Tissue ◽

Proximal Tubule Cell ◽

Ang Ii ◽

Sprague Dawley ◽

Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

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