Aldosterone receptor antagonism exacerbates intrarenal angiotensin II augmentation in ANG II-dependent hypertension

Effects of aldosterone receptor (AR) blockade with eplerenone (epl) on renal Na+ excretion, arterial blood pressure, intra-adrenal and renal ANG II, and plasma aldosterone levels during ANG II-dependent hypertension were evaluated. Rats from one cohort ( n = 10/group) 1) control, 2) control + epl (25 mg/day), 3) ANG II (60 ng/min), and 4) ANG II + epl were maintained in metabolic cages for 28 days for daily urine collections. Systolic blood pressure (SBP) was measured weekly by tail-cuff. In a second cohort ( n = 12/group), daily SBP was measured by telemetry ( n = 6 rats/group) 1) control, 2) ANG II, and 3) ANG II + epl. A diet containing epl (0.1%) was provided after 1 wk of ANG II infusion. Direct monitoring of BP by telemetry showed that epl delayed the onset of the increase in SBP by 2 days and slightly reduced SBP (186 ± 6 vs. 177 ± 8 mmHg). Epl transiently increased Na+ excretion within 24 h of treatment in both normo- and hypertensive rats; however, balance was reestablished within 5 days suggesting that alternative mechanisms for conserving Na+ are activated. Cortical α-epithelial Na+ channel content (α-ENaC) was not altered after 21 days of epl treatment. Epl exacerbated the ANG II-mediated increases in intrarenal ANG II (226 ± 16 vs. 365 ± 38 fmol/g) and further increased intra-adrenal ANG II (3.9 ± 0.3 vs. 8.2 ± 0.9 fmol/mg) and aldosterone (255 ± 55 vs. 710 ± 87 pmol/mg) content. Exacerbation of intrarenal ANG II levels likely contributes to the maintenance of α-ENaC protein content and thus Na+ reabsorption, which helps explain the ineffectiveness of AR blockade in reducing SBP in ANG II-infused models of hypertension.

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Chronic Intermittent Hypobaric Hypoxia Decreases High Blood Pressure by Stabilizing the Vascular Renin-Angiotensin System in Spontaneously Hypertensive Rats

Frontiers in Physiology ◽

10.3389/fphys.2021.639454 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hua Chen ◽

Bin Yu ◽

Xinqi Guo ◽

Hong Hua ◽

Fang Cui ◽

...

Keyword(s):

Blood Pressure ◽

Hypobaric Hypoxia ◽

Renin Angiotensin System ◽

Mesenteric Arteries ◽

Ang Ii ◽

Hypertensive Rats ◽

Angiotensin System ◽

Spontaneously Hypertensive ◽

Arterial Blood ◽

Tnf Α

Background and AimsPrevious studies have demonstrated the anti-hypertensive effect of chronic intermittent hypobaric hypoxia (CIHH) in hypertensive rats. The present study investigated the anti-hypertensive effect of CIHH in spontaneously hypertensive rats (SHR) and the role of the renin-angiotensin system (RAS) in anti-hypertensive effect of CIHH.MethodsFifteen-week-old male SHR and WKY rats were divided into four groups: the SHR without CIHH treatment (SHR-CON), the SHR with CIHH treatment (SHR-CIHH), the WKY without CIHH treatment (WKY-CON), and the WKY with CIHH treatment (WKY-CIHH) groups. The SHR-CIHH and WKY-CIHH rats underwent 35-days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h per day. Arterial blood pressure and heart rate were recorded by biotelemetry, and angiotensin (Ang) II, Ang1–7, interleukin (IL)-6, tumor necrosis factor-alpha (TNF)-α, and IL-10 in serum and the mesenteric arteries were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. The microvessel tension recording technique was used to determine the contraction and relaxation of the mesenteric arteries. Hematoxylin and eosin and Masson’s staining were used to observe vascular morphology and fibrosis. Western blot was employed to detect the expression of the angiotensin-converting enzyme (ACE), ACE2, AT1, and Mas proteins in the mesenteric artery.ResultsThe biotelemetry result showed that CIHH decreased arterial blood pressure in SHR for 3–4 weeks (P < 0.01). The ELISA and immunohistochemistry results showed that CIHH decreased Ang II, but increased Ang1–7 in serum and the mesenteric arteries of SHR. In the CIHH-treated SHR, IL-6 and TNF-α decreased in serum and the mesenteric arteries, and IL-10 increased in serum (P < 0.05–0.01). The microvessel tension results revealed that CIHH inhibited vascular contraction with decreased Ang1–7 in the mesenteric arteries of SHR (P < 0.05–0.01). The staining results revealed that CIHH significantly improved vascular remodeling and fibrosis in SHR. The western blot results demonstrated that CIHH upregulated expression of the ACE2 and Mas proteins, and downregulated expression of the ACE and AT1 proteins (P < 0.05–0.01).ConclusionCIHH decreased high blood pressure in SHR, possibly by inhibiting RAS activity, downregulating the ACE-Ang II-AT1 axis and upregulating the ACE2-(Ang1-7)-Mas axis, which resulted in antagonized vascular remodeling and fibrosis, reduced inflammation, and enhanced vascular relaxation.

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Cardiovascular Effects of Micromeria graeca (L.) Benth. ex Rchb in Normotensive and Hypertensive Rats

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530319666191206163136 ◽

2020 ◽

Vol 20 (8) ◽

pp. 1253-1261

Author(s):

Mourad Akdad ◽

Mohamed Eddouks

Keyword(s):

Blood Pressure ◽

Cardiovascular System ◽

Arterial Blood Pressure ◽

Antihypertensive Activity ◽

Computer Assisted ◽

Hypertensive Rats ◽

Vasorelaxant Effect ◽

Arterial Blood

Aims: The present study was performed in order to analyze the antihypertensive activity of Micromeria graeca (L.) Benth. ex Rchb. Background: Micromeria graeca (L.) Benth. ex Rchb is an aromatic and medicinal plant belonging to the Lamiaceae family. This herb is used to treat various pathologies such as cardiovascular disorders. Meanwhile, its pharmacological effects on the cardiovascular system have not been studied. Objective: The present study aimed to evaluate the effect of aqueous extract of aerial parts of Micromeria graeca (AEMG) on the cardiovascular system in normotensive and hypertensive rats. Methods: In this study, the cardiovascular effect of AEMG was evaluated using in vivo and in vitro investigations. In order to assess the acute effect of AEMG on the cardiovascular system, anesthetized L-NAME-hypertensive and normotensive rats received AEMG (100 mg/kg) orally and arterial blood pressure parameters were monitored during six hours. In the sub-chronic study, rats were orally treated for one week, followed by blood pressure assessment during one week of treatment. Blood pressure was measured using a tail-cuff and a computer-assisted monitoring device. In the second experiment, isolated rat aortic ring pre-contracted with Epinephrine (EP) or KCl was used to assess the vasorelaxant effect of AEMG. Results: Oral administration of AEMG (100 mg/kg) provoked a decrease of arterial blood pressure parameters in hypertensive rats. In addition, AEMG induced a vasorelaxant effect in thoracic aortic rings pre-contracted with EP (10 μM) or KCl (80 mM). This effect was attenuated in the presence of propranolol and methylene blue. While in the presence of glibenclamide, L-NAME, nifedipine or Indomethacin, the vasorelaxant effect was not affected. Conclusion: This study showed that Micromeria graeca possesses a potent antihypertensive effect and relaxes the vascular smooth muscle through β-adrenergic and cGMP pathways.

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Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00223.2014 ◽

2015 ◽

Vol 308 (10) ◽

pp. C803-C812 ◽

Cited By ~ 20

Author(s):

Colin N. Young ◽

Anfei Li ◽

Frederick N. Dong ◽

Julie A. Horwath ◽

Catharine G. Clark ◽

...

Keyword(s):

Blood Pressure ◽

Endoplasmic Reticulum ◽

Transcription Factor ◽

Angiotensin Ii ◽

Er Stress ◽

Bioluminescence Imaging ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Ang Ii ◽

Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

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Abstract P489: Effect of Continuous Intake of Hesperidin on Blood Pressure in 2-kidney, 1-clip Renovasucular Hypertensive Rats

Hypertension ◽

10.1161/hyp.70.suppl_1.p489 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Ayuna Yamaoka ◽

Yukiko Segawa ◽

Saki Maruyama ◽

Natsumi Saito ◽

Hiroko Hashimoto ◽

...

Keyword(s):

Blood Pressure ◽

Mrna Expression ◽

Control Diet ◽

Left Renal Artery ◽

Sham Operation ◽

Hypertensive Rats ◽

Fruit Peel ◽

Arterial Blood ◽

Significant Difference ◽

Enos Mrna

Objective: Hesperidin (HES) is a flavonoid which is contained in citrus fruit peel. It has physiological effects on blood vessels such as strengthening capillary vessels. Thus, it is known to be one of the effective ingredients of herbal medicine. Some studies have shown that the intake of HES decreases blood pressure (BP) in spontaneously hypertensive rats. The antihypertensive effect of HES is suggested to be due to vasodilation by nitric oxide (NO). However, its mechanism has not been clarified in detail. In this study, we observed whether HES intake decreases BP in 2-kidney, 1-clip renovasucular hypertensive rats (2K1C) and evaluated endothelial NO synthase (eNOS) mRNA to investigate its role in the mechanism. Methods: Male Sprague-Dawley rats (6 weeks old) were treated with sham operation (SHAM) or clipping the left renal artery (2K1C). After surgery, the rats started receiving continuously a control diet (C) or a diet containing 0.1% (w/w) HES for 6 weeks. The systolic BP (SBP) was measured by a tail-cuff method every week. At the end of the protocol, mean arterial blood pressure (MAP) was measured in each rat under anesthesia. Then, the aortas were removed for extracting mRNA. eNOS mRNA expression was evaluated using real-time RT-PCR. Results: At the end of the protocol, SBP in 2K1C-C was significantly higher than in SHAM-C (170±6 vs 117±6 mmHg, p <0.001). On the other hand, 2K1C-HES was lower in SBP (141±4 mmHg) than 2K1C-C ( p <0.01). There were no significant differences between SHAM-HES (122±7 mmHg) and SHAM-C. MAP at the end of the protocol were similar to in SBP. ANOVA revealed mRNA expression of eNOS was significantly higher in 2K1C than in SHAM ( p <0.05), and showed no significant difference between C and HES, nor a significant interaction. Conclusion: Continuous intake of HES may suppress BP increase in 2K1C. The role of eNOS mRNA expression may not be involved in the mechanism.

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Abstract P059: A A Role of Aminopeptidase A in the Brain on Cardiovascular Regulation of Conscious Rat

Hypertension ◽

10.1161/hyp.66.suppl_1.p059 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Takuto Nakamura ◽

Masanobu Yamazato ◽

Akio Ishida ◽

Yusuke Ohya

Keyword(s):

Blood Pressure ◽

Protein Expression ◽

Drinking Behavior ◽

Cardiovascular Regulation ◽

Ang Ii ◽

Hypertensive Rats ◽

Aminopeptidase A ◽

The Brain

Objective: Aminopeptidase A (APA) have important role in conversion of Ang II to Ang III. Intravenous APA administration lowers blood pressure in hypertensive rats. In contrast, APA inhibition in the brain lowers blood pressure in hypertensive rats. Therefore APA might have different role on cardiovascular regulation. However, a role of APA and Ang III on cardiovascular regulation especially in the brain has not been fully understood. Our purpose of present study was to investigate a role of APA and Ang III in the brain on cardiovascular regulation in conscious state. Method: 12-13 weeks old Wistar Kyoto rat (WKY) and 12-16 weeks old spontaneously hypertensive rat (SHR) were used. i) APA distribution in the brain was evaluated by immunohistochemistry. Protein expression of APA was evaluated by Western blotting. Enzymatic activity of APA was evaluated using L-glutamic acid γ-(4-nitroanilide) as a substrate. ii) WKY received icv administration of Ang II 25ng/2μL and Ang III 25ng/2μL. We recorded change in mean arterial pressure (MAP) in conscious and unrestraied state and measured induced drinking time. iii) SHR received icv administeration of recombinant APA 400ng/4μL. We recorded change in MAP in conscious and unrestraied state and measured induced drinking time. Result: i) APA was diffusely immunostained in the cells of brain stem including cardiovascular regulatory area such as rostral ventrolateral medulla. Protein expression and APA activity in the brain were similar between WKY (n=3) and SHR (n=3).ii) Icv administration of Ang II increased MAP by 33.8±3.8 mmHg and induced drinking behavior for 405±90 seconds (n=4). Icv administration of Ang III also increased MAP by 24.7±2.4 mmHg and induced drinking behavior for 258±62 seconds (n=3). These vasopressor activity and induced drinking behavior was completely blocked by pretretment of angiotensin receptor type 1 blocker.iii) Icv administration of APA increased MAP by 10.0±1.7 mmHg (n=3). Conclusion: These results suggested that Ang III in the brain increase blood pressure by Angiotensin type 1 receptor dependent mechanism and APA in the brain may involved in blood pressure regulation as a vasopressor enzyme.

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Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.262.6.e763 ◽

1992 ◽

Vol 262 (6) ◽

pp. E763-E778 ◽

Cited By ~ 136

Author(s):

I. A. Reid

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Sympathetic Nervous System ◽

Blood Pressure Control ◽

Cardiovascular Responses ◽

Pressure Control ◽

Ang Ii ◽

Arterial Blood ◽

Baroreceptor Reflexes ◽

Sympathetic Nervous

The renin-angiotensin system plays an important role in the regulation of arterial blood pressure and in the development of some forms of clinical and experimental hypertension. It is an important blood pressure control system in its own right but also interacts extensively with other blood pressure control systems, including the sympathetic nervous system and the baroreceptor reflexes. Angiotensin (ANG) II exerts several actions on the sympathetic nervous system. These include a central action to increase sympathetic outflow, stimulatory effects on sympathetic ganglia and the adrenal medulla, and actions at sympathetic nerve endings that serve to facilitate sympathetic neurotransmission. ANG II also interacts with baroreceptor reflexes. For example, it acts centrally to modulate the baroreflex control of heart rate, and this accounts for its ability to increase blood pressure without causing a reflex bradycardia. The physiological significance of these actions of ANG II is not fully understood. Most evidence indicates that the actions of ANG to enhance sympathetic activity do not contribute significantly to the pressor response to exogenous ANG II. On the other hand, there is considerable evidence that the actions of endogenous ANG II on the sympathetic nervous system enhance the cardiovascular responses elicited by activation of the sympathetic nervous system.

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Evaluation of the Accuracy of the Delta Life DL 1000 Oscillometric Monitor for Blood Pressure Measurement in Anesthetized Dogs of Different Weight Ranges

Acta Scientiae Veterinariae ◽

10.22456/1679-9216.105229 ◽

2020 ◽

Vol 48 ◽

Author(s):

Bárbara Silva Correia ◽

Eduardo Raposo Monteiro ◽

João Victor Barbieri Ferronatto ◽

Luciana Branquinho Queiroga ◽

José Ricardo Herrera Becerra

Keyword(s):

Blood Pressure ◽

Arterial Blood Pressure ◽

Pressure Measurement ◽

Elective Surgery ◽

Blood Pressure Measurement ◽

Measurement Data ◽

Arterial Blood ◽

Anesthetized Dogs ◽

Group 2 ◽

Group 1

Background: Arterial blood pressure is one of the most commonly variables monitored during anesthetic procedures in veterinary patients. The most reliable method for measuring arterial blood pressure in dogs and cats is the direct (invasive) method. However, the oscillometric method is less complex and more practical for clinical routine in small animals. Nevertheless, oscillometric monitors present great variability in accuracy. The present study aimed to determine the accuracy of the Delta Life DL 1000 oscillometric monitor for measurement of systolic, mean and diastolic blood pressures (SAP, MAP and DAP, respectively) in anesthetized dogs of different weight ranges.Materials, Methods & Results: This study was approved by the Institutional Ethics Committee of Animal Use. Fifteen female dogs of different breeds, weighing 11.6 ± 10.0 kg and with a mean age of 48 ± 51 months were used. All animals were scheduled for elective surgery under general anesthesia in the Institution Veterinary Hospital. Dogs were anesthetized with morphine, propofol and isoflurane and had one 20 or 22 gauge catheter introduced into the dorsal pedal artery for continuous, invasive monitoring of SAP, MAP and DAP. A blood pressure cuff was positioned over the middle third of the radius and connected to Delta Life DL 1000 monitor. Oscillometric readings of SAP, MAP and DAP were registered every 5 minutes, and invasive values were simultaneously recorded. Values obtained with both methods were compared (invasive versus oscillometric) by use of the Bland Altman method to determine the bias, standard deviation of bias and 95% limits of agreement. The percentages of errors between the methods within 10 mmHg and within 20 mmHg were calculated. The results obtained were compared with the criteria from the American College of Veterinary Internal Medicine (ACVIM) for validation of indirect methods of arterial blood pressure measurement. Data were stratified into two groups according to the weight: < 10 kg (Group 1; n = 9); and ≥ 10 kg (Group 2; n = 6). In Group 1, 119 paired measurements were obtained, four of which classified as hypotension (SAP < 90 mmHg), 98 as normotension (SAP from 90 to 140mmHg) and 17 as hypertension (SAP > 140 mmHg). Bias (± SD) values in Group 1 were as follows: SAP, 5.2 ± 18.1 mmHg; MAP, -3.4 ± 17.2 mmHg; and DAP, 12.0 ± 17.5 mmHg. The percentages of errors within 10 mmHg were 40.3% for SAP; 45.4% for MAP and 28.6% for DAP. The percentages of errors within 20 mmHg were 72.3% for SAP, 84.0% for MAP and 68.1% for DAP. In Group 2, 66 paired measurements were obtained, nine of which classified as hypotension, 56 as normotension and one as hypertension. Bias (± SD) in Group 2 were as follows: SAP, 13.6 ± 14.3 mmHg; MAP, -1.1 ± 13.5 mmHg; and DAP, 8.2 ± 16.0 mmHg. The percentages of errors within 10 mmHg were 33.3% for SAP, 77.3% for MAP and 33.3% for DAP. The percentages of errors within 20 mmHg were 65.1% for SAP, 92.4% for MAP and 83.4% for DAP.Discussion: Based on the results of this study and reference criteria from the ACVIM, the Delta Life DL 1000 monitor had a poor accuracy for SAP, MAP and DAP and did not meet the criteria from the ACVIM in anesthetized dogs under 10 kg. Measurements of MAP in dogs ≥ 10 kg met the ACVIM criteria, but measurements of SAP and DAP did not. Based on the findings in this study, the DL 1000 oscillometric monitor is not recommended for blood pressure measurement in anesthetized dogs < 10 kg. In dogs ≥ 10 kg, measurements of MAP yielded acceptable values, but SAP and DAP measurements did not.

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REDUCTION OF ARTERIAL BLOOD PRESSURE OF HYPERTENSIVE PATIENTS AND ANIMALS WITH EXTRACTS OF KIDNEYS

Journal of Experimental Medicine ◽

10.1084/jem.73.1.7 ◽

1941 ◽

Vol 73 (1) ◽

pp. 7-41 ◽

Cited By ~ 24

Author(s):

Irvine H. Page ◽

O. M. Helmer ◽

K. G. Kohlstaedt ◽

P. J. Fouts ◽

G. F. Kempf

Keyword(s):

Blood Pressure ◽

Arterial Blood Pressure ◽

Malignant Hypertension ◽

Hypertensive Rats ◽

Hypertensive Patients ◽

Arterial Blood ◽

Lower Blood ◽

Mean Pressure ◽

Activity Loss ◽

Experimental Stage

1. Extracts of kidneys have been prepared containing a substance which lowers arterial blood pressure for prolonged periods in patients with essential and malignant hypertension, and in hypertensive dogs and rats. 2. Several different chemical procedures are proposed for the preparation of the extract. The best one has not been decided upon. 3. The quantity of original fresh whole kidney required to yield enough extract to lower blood pressure from hypertensive levels (200 mm. Hg mean pressure) to normal levels is roughly 600 to 900 gm. in dogs within 4 to 8 days. In hypertensive patients the yield from 700 to 1000 gm. daily for several weeks may be necessary. 4. Lowering of the blood pressure too rapidly in animals results in a shock syndrome which may be fatal. If overdosage is avoided, no appreciable rise in blood urea nitrogen occurs, nor do other signs of toxicity appear. 5. Lowering of blood pressure to nearly normal levels has been accomplished in 60 hypertensive dogs, and in some of these it has been allowed to rise and was again reduced as many as five times. Similar results have been obtained with hypertensive rats. 6. Six patients with essential hypertension have been treated resulting in prolonged reduction of blood pressure. Clinically the patients appear improved. 7. Five patients with malignant hypertension have been treated, with reduction of the blood pressure in all instances. One patient was treated despite urea clearance of 5 per cent of normal. His blood pressure was sharply reduced, but death in uremia occurred. The second patient also exhibited sharp reduction of pressure and died after treatment was discontinued. The other three are much improved after treatment, as indicated by increase in vision and mental activity, loss of dyspnea, improvement in the electrocardiogram, etc. 8. The length of time the blood pressure remains lowered varies greatly in both animals and man. The trend is usually upwards after discontinuing treatment for 4 to 6 days. 9. Increasing experience with this treatment suggests that it is of value in the management of hypertension, but it is yet in the experimental stage.

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Abstract 9: Endothelin B Receptors Protect Against Hypertension Induced by Chronic Angiotensin II in Female Rats

Hypertension ◽

10.1161/hyp.60.suppl_1.a9 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Wararat Kittikulsuth ◽

David M Pollock

Keyword(s):

Blood Pressure ◽

High Salt ◽

Female Rats ◽

Male Rats ◽

Ang Ii ◽

Hypertensive Rats ◽

High Salt Diet ◽

Male And Female ◽

Male And Female Rats ◽

Endothelin B

Endothelin B (ET B ) receptors mediate vasodilation, anti-inflammation and natriuresis, which ultimately contribute to blood pressure control. We previously showed that renal medullary ET B receptor function is maintained in female angiotensin (Ang) II hypertensive rats, while male Ang II hypertensive rats have blunted ET B -induced natriuretic responses. Because female rats are more resistance to blood pressure elevation induced by high salt intake and/or Ang II infusion, we hypothesized that ET B receptors protect female rats against the hypertensive response and renal injury induced by a high salt diet and chronic Ang II infusion compared to males. Male and female rats received Ang II infusion (150 ng/kg/min; sc.) with 4% NaCl for 4 weeks; blood pressure was measured by telemetry. After a week of Ang II infusion with a high salt diet, subsets of both male and female rats received the ET B antagonist, A-192621, at three doses on consecutive weeks (1, 3, and 10 mg/kg/d in food). Male rats had a significantly higher blood pressure compared to females after 4 weeks of Ang II (178±10 vs. 138±10 mmHg; p<0.05). A-192621 resulted in a dose-dependent increase in blood pressure in female Ang II hypertensive rats (167±8 mmHg at 10 mg/kg/d; p<0.05); the increase produced by A-192621 in male Ang II hypertensive rats was not statistically significant (193±10 mmHg). After 4 weeks of Ang II infusion, the level of proteinuria and nephrinuria was higher in male rats compared to female. A-192621 did not further increase urinary excretion of protein or nephrin in both male and female Ang II hypertensive rats. In conclusion, these results support the hypothesis that ET B receptors provide more protection against hypertension during chronic Ang II infusion in female rats compared to male.

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Abstract 065: Overexpression of an Intracellular Angiotensin II Fusion Protein Selectively in the Mitochondria of the Proximal Tubules Elevates Blood Pressure in Mice via AT 1a Receptor-mediated Mitochondrial Respiratory and Glycolysis Stress

Hypertension ◽

10.1161/hyp.68.suppl_1.065 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Xiao C Li ◽

Manoocher Soleimani ◽

Hoang Nguyen ◽

Hong Li ◽

Jia L Zhuo

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Fusion Protein ◽

Proximal Tubule ◽

Physiological Role ◽

Proximal Tubules ◽

Ang Ii ◽

Stress Tests ◽

Arterial Blood ◽

Mitochondrial Respiratory

An intracrine mitochondrial renin-angiotensin system (RAS) has recently been identified in various animal and human tissues, but whether the mitochondrial RAS plays a physiological role in the regulation of blood pressure remains unknown. The present study tested whether overexpression of an intracellular angiotensin II fusion protein, ECFP/ANG II, selectively in the mitochondria of the proximal tubules alters blood pressure, and whether the effects may involve AT 1a receptors and the Na + /H + exchanger 3 (NHE3). An adenoviral vector encoding ECFP/ANG II, a mitochondria targeting sequence, and the sglt2 promoter, Ad-sglt2-mito-ECFP/ANG II, was constructed for proximal tubule- and mitochondria-specific overexpression for 2 weeks. In adult male C57BL/6J mice, overexpression of mito-ECFP/ANG II in the mitochondria of the proximal tubules increased systolic blood pressure (SBP) significantly (Control: 116 ± 3 vs. mito-ECFP/ANG II: 128 ± 3 mmHg; p <0.01, n=15). The blood pressure-increasing effect of Ad-sglt2-mito-ECFP/ANG II was blocked in proximal tubule-specific AT 1a -KO mice (Control: 105 ± 2 vs. mito-ECFP/ANG II: 104 ± 4 mmHg; n.s ., n=7), or in proximal tubule-specific NHE3-KO mice (Control: 108 ± 3 vs. mito-ECFP/ANG II: 107 ± 3 mmHg; n.s ., n=13), respectively. In further experiments, mouse proximal tubule cells were transfected with Ad-sglt2-mito-ECFP/ANG II for 48 h and treated with the AT 1 blocker losartan (10 μM) or the AT 2 blocker PD123319 (10 μM) to measure mitochondrial respiratory and glycolytic function using Seahorse XF Cell Mito and XF Glycolysis Stress Tests. The mito-ECFP/ANG II expression was robust and colocalized with MitoTracker® Red FM. Overexpression of mito-ECFP/ANG II markedly increased oxygen consumption rate (OCR) (Control: 139.4 ± 9.2 vs. mito-ECFP/ANG II: 236.3 ± 12.6 pmol/min; p <0.01, n=12) and extracellular acidification rate (ECAR) (Control: 8.8 ± 0.6 vs. mito-ECFP/ANG II: 11.8 ± 1.2 mpH/min; p <0.01, n=12), respectively. Losartan blocked the effects of mito-ECFP/ANG II on OCR and ECAR, whereas PD123319 had no effect. We conclude that intracellular ANG II may activate AT 1 receptors in the mitochondria of the proximal tubules to alter mitochondrial respiratory and glycolytic function and arterial blood pressure.

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