Role of vasoconstrictors in the systemic hypertension of rats acclimatized to hypoxia

Exposure to hypoxia (2–5 wk) results in systemic hypertension in rats and in humans. The possible mechanism(s) was investigated in rats acclimatized for 3 wk to barometric pressure of approximately 370 Torr (A) and in nonacclimatized littermates (NA) by administration of alpha-adrenergic [phentolamine (PHLM)], angiotensin II (ANG II), and arginine vasopressin (AVP V1) receptor antagonists. Both A and NA rats were studied in hypoxia (inspiratory O2 fraction = 0.10). Baseline mean arterial blood pressure (MABP) was higher in A than in NA rats: 126 +/- 4 vs. 101 +/- 2 mmHg (P < 0.05). Neither ANG II nor AVP V1 receptor antagonist influenced baseline MABP; however, both contributed to MABP recovery after PHLM. After simultaneous blockade of ANG II and AVP V1, PHLM lowered MABP by 65 +/- 2 and 45 +/- 3 mmHg in A and NA rats, respectively (P < 0.05). After combined blockade of the three systems, the smooth muscle relaxant sodium nitroprusside did not further modify MABP, which remained higher in A rats. It is concluded that 1) the hypertension in A rats is partly due to a higher alpha-adrenergic tone, 2) neither ANG II nor AVP contributes to the hypertension, but ANG II and AVP participate in MABP control after PHLM, 3) no other vasoconstrictor agents operate in either group, and 4) the higher MABP in A rats after sodium nitroprusside may reflect additional hypertensive mechanisms.

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Role of arteria baroreceptor input on thirst and urinary responses to intracerebroventricular angiotensin II

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.3.r591 ◽

1993 ◽

Vol 265 (3) ◽

pp. R591-R595 ◽

Cited By ~ 4

Author(s):

R. L. Thunhorst ◽

S. J. Lewis ◽

A. K. Johnson

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Arterial Blood Pressure ◽

Water Intake ◽

Enzyme Inhibitor ◽

Ang Ii ◽

Converting Enzyme ◽

Arterial Blood ◽

Endogenous Formation

Intracerebroventricular (icv) infusion of angiotensin II (ANG II) in rats elicits greater water intake under hypotensive, compared with normotensive, conditions. The present experiments used sinoaortic baroreceptor-denervated (SAD) rats and sham-operated rats to examine if the modulatory effects of arterial blood pressure on water intake in response to icv ANG II are mediated by arterial baroreceptors. Mean arterial blood pressure (MAP) was raised or lowered by intravenous (i.v.) infusions of phenylephrine (1 or 10 micrograms.kg-1 x min-1) or minoxidil (25 micrograms.kg-1 x min-1), respectively. The angiotensin-converting enzyme inhibitor captopril (0.33 mg/min) was infused i.v. to prevent the endogenous formation of ANG II during testing. Urinary excretion of water and solutes was measured throughout. Water intake elicited by icv ANG II was inversely related to changes in MAP. Specifically, rats drank more water in response to icv ANG II when MAP was reduced by minoxidil but drank less water when MAP was elevated by phenylephrine. The influence of changing MAP on the icv ANG II-induced drinking responses was not affected by SAD. These results suggest that the modulatory effects of arterial blood pressure on icv ANG II-induced drinking can occur in the absence of sinoaortic baroreceptor input.

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Role of the area postrema in angiotensin II modulation of baroreflex control of heart rate in conscious mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00793.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. H1003-H1007 ◽

Cited By ~ 18

Author(s):

Baojian Xue ◽

Hope Gole ◽

Jaya Pamidimukkala ◽

Meredith Hay

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Angiotensin Ii ◽

Arterial Pressure ◽

Area Postrema ◽

Ang Ii ◽

Baroreflex Control ◽

Arterial Blood ◽

Intravenous Infusions

This study reports the effects of angiotensin II (ANG II), arginine vasopression (AVP), phenylephrine (PE), and sodium nitroprusside (SNP) on baroreflex control of heart rate in the presence and absence of the area postrema (AP) in conscious mice. In intact, sham-lesioned mice, baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of ANG II were significantly less than those observed with similar increases in arterial pressure with PE (slope: −3.0 ± 0.9 vs. −8.1 ± 1.5 beats · min−1 · mmHg−1). Baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of AVP were the same as those observed with PE in sham animals (slope: −5.8 ± 0.7 vs. −8.1 ± 1.5 beats · min−1 · mmHg−1). After the AP was lesioned, the slope of baroreflex inhibition of heart rate was the same whether pressure was increased with ANG II, AVP, or PE. The slope of the baroreflex-induced increases in heart rate due to decreases in arterial blood pressure with SNP were the same in sham- and AP-lesioned animals. These results indicate that, similar to other species, in mice the ability of ANG II to acutely reset baroreflex control of heart rate is dependent on an intact AP.

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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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The effects of estradiol and testosterone on renal tissues oxidative after central injection of angiotensin II in female doca – salt treated rats

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2018-0044 ◽

2018 ◽

Vol 37 (3) ◽

Cited By ~ 1

Author(s):

Marzieh Kafami ◽

Mahmoud Hosseini ◽

Saeed Niazmand ◽

Esmaeil Farrokhi ◽

Mosa Al-Reza Hajzadeh ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Sex Hormones ◽

Active Oxygen Species ◽

Oxygen Species ◽

Research Needs ◽

Ang Ii ◽

Detailed Mechanism ◽

Female Wistar Rats

Abstract Background Although numerous studies have proven that estrogen (Est) has a protective effect on the development of hypertension, more research needs to be done to show its detailed mechanism in a variety of hypertension. The important role of active oxygen species in blood pressure is well defined. We examined whether or not sex hormones change the growth of reactive oxygen species (ROS) ‎in kidneys after central microinjection of angiotensin II (Ang II).‎ Materials and methods Female Wistar rats, 8 weeks old (200 ± 10 g) were used in this study. The animal groups were (1) Sham, (2) Ovariectomy (OVX), (3) Sham-Hypertension (Sham-Hyper), (4) OVX-Hypertension (OVX-Hyper), (5) Sham-Hyper-Est, (6) OVX-Hyper-Est‎;‎ (7) Sham-Hyper-Testosterone (Tst) and (8) OVX-Hyper-Tst. Solutions of 1% NaCl and 0.1 KCl ‎were used and desoxycorticostrone (doca-salt) was injected (45 mg/kg) 3 times a week in Hypertension groups. Estradiol and Tst (2 mg/kg and ‎5 mg/kg‎; daily; subcutaneously) for 4 weeks. Ang II (50 μM, 5 μL) was microinjected by intracerebroventricular ( i.c.v.) infusion and malondialdehyde (MDA) and thiol in the kidneys were measured. Results MDA in the kidneys was increased by Ang II and doca-salt treatments. Both estradiol and Tst decreased the kidney’s MDA. The level of thiol was higher in Hyper ‎groups and reversed after treatment with estradiol and Tst. Conclusions Our findings suggest that central effect of Ang II on blood pressure and kidney ‎disease is accompanied with increased levels of oxidative stress in the kidneys. Indeed sex hormones change the ROS level in the kidneys after central ‎microinjection of Ang II.‎‎

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Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology

International Journal of Molecular Sciences ◽

10.3390/ijms21124525 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4525

Author(s):

Amanda St. Paul ◽

Cali B. Corbett ◽

Rachael Okune ◽

Michael V. Autieri

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Vascular Smooth Muscle ◽

Vascular Diseases ◽

Reduce Blood Pressure ◽

Vascular Pathology ◽

Lipid Lowering ◽

Ang Ii

Cardiovascular disease is the leading cause of morbidity and mortality in the Western and developing world, and the incidence of cardiovascular disease is increasing with the longer lifespan afforded by our modern lifestyle. Vascular diseases including coronary heart disease, high blood pressure, and stroke comprise the majority of cardiovascular diseases, and therefore represent a significant medical and socioeconomic burden on our society. It may not be surprising that these conditions overlap and potentiate each other when we consider the many cellular and molecular similarities between them. These intersecting points are manifested in clinical studies in which lipid lowering therapies reduce blood pressure, and anti-hypertensive medications reduce atherosclerotic plaque. At the molecular level, the vascular smooth muscle cell (VSMC) is the target, integrator, and effector cell of both atherogenic and the major effector protein of the hypertensive signal Angiotensin II (Ang II). Together, these signals can potentiate each other and prime the artery and exacerbate hypertension and atherosclerosis. Therefore, VSMCs are the fulcrum in progression of these diseases and, therefore, understanding the effects of atherogenic stimuli and Ang II on the VSMC is key to understanding and treating atherosclerosis and hypertension. In this review, we will examine studies in which hypertension and atherosclerosis intersect on the VSMC, and illustrate common pathways between these two diseases and vascular aging.

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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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Abstract 7: Angiotensin II Type 2 Receptor Deficiency Increases Renal ACE/ACE2 Ratio-Ang II-AT1R Expression In Male but not in Female Mice

Hypertension ◽

10.1161/hyp.60.suppl_1.a7 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Quaisar Ali ◽

Yonnie Wu ◽

Tadashi Inagami ◽

Tahir Hussain

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Angiotensin Ii ◽

Renin Activity ◽

Ang Ii ◽

Male And Female ◽

Female Mice ◽

Gender Specific

Angiotensin II acting via Angiotensin II type 2 receptors (AT2Rs) is believed to be protective against blood pressure increase and affects renal function under pathophysiological condition. Recently we have observed that stimulation of AT2Rs in male obese Zucker rats has shifted the two opposing arms of renin angiotensin system (RAS) i.e. ACE-Ang II-AT1 vs ACE2/Ang-(1-7)-Mas. Evidence suggests that estrogen regulates RAS, including AT2R in female mice. We hypothesized that AT2R has a gender specific regulation of RAS. In the present study, we investigated the role of AT2Rs in regulating RAS components in male and female mice. Kidney cortex from AT2R knockout (AT2RKO) male and female mice and wild type (WT) with similar background (C57BL/6) of 20 weeks of age were used in the study. The cortical ACE expression (ng ACE/μg tissue) was significantly increased in AT2RKO mice (3±0.02) compared to WT males (1.9±0.02). LC/MS analysis of cortical tissue revealed that Ang II was also significantly increased in AT2RKO mice (WT: 31±3, AT2RKO: 47±3 fmoles/mg tissue). Deletion of AT2R significantly increased AT1R (204%, 204 of 100) expression and had no effect on renin activity compared to WT males. The cortical expression of ACE2 activity (WT: 113±8, AT2RKO: 40±11, RFU/min), Ang-(1-7) levels (WT: 7.3±1.4, AT2RKO: 3±0.8 fmoles/mg tissue) and Mas receptor (AT2RKO: 54±15, % of WT) was significantly decreased in AT2RKO males compared to WT. The cortical expression of the AT2R and MasR was 2-fold greater in WT females compared to WT male. The renin activity (WT: 32±2, AT2RKO: 21±0.3, RFU/min) and MasR expression (WT: 187.5±55, AT2KO: 47±9) was significantly decreased in AT2RKO females compared to the female WT. Interestingly, Ang-(1-7) level (WT: 5.7±0.7, AT2RKO 2.6±0.7 fmoles/mg tissue) was decreased but no changes in ACE or ACE2 activity was observed in AT2KO females compared to their WT, suggesting a role of non-ACE2 pathway. This study suggests that AT2R regulates ACE/ACE2 ratio-Ang II-AT1R expression negatively only in males, whereas in females, it regulates Ang-(1-7) potentially via non-ACE2 pathway. Such changes indicate a gender specific mechanisms potentially associated with AT2R-mediated regulation of renal function and blood pressure control.

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Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Mediators of Inflammation ◽

10.1155/2020/5741047 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Yunzhao Yang ◽

Shaoqun Tang ◽

Chunchun Zhai ◽

Xin Zeng ◽

Qingjian Liu ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Inflammatory Response ◽

Vascular Dysfunction ◽

Control Group ◽

Dependent Manner ◽

Ang Ii ◽

Stat3 Pathway

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

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Role of endothelin receptors in the hypertensive state of kinin B2 knockout mice subjected to a high-salt diet

Clinical Science ◽

10.1042/cs103s380s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 380S-384S ◽

Cited By ~ 13

Author(s):

Isabelle BROCHU ◽

Julie LABONTÉ ◽

Ghassan BKAILY ◽

Pedro D'ORLÉANS-JUSTE

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Receptor Antagonist ◽

Tap Water ◽

Blood Pressure Measurement ◽

Rna Extraction ◽

Angiotensin Receptors ◽

Rt Pcr ◽

Arterial Blood

Mice with disruption of the kinin B2 receptor (B2KO mice) are sensitive to salt-rich diets, which causes hypertension. The aim of the study was to assess the role of endothelin-1 (ET-1) and angiotensin-II in hypertensive B2KO mice on a salt-rich diet. We also wanted to verify if there is an upregulation of the mRNA expression of the precursors or receptors for these hormones. Two groups of B2KO mice (20–25g) were investigated. The first group received an 8% NaCl diet with 1% NaCl in drinking water (HS) and the second was fed with normal food with tap water (NS). The antagonists tested were the ETA receptor antagonist BQ-123 (1 and 5mg/kg), the ETB receptor antagonist BQ-788 (0.25 and 1mg/kg), the angiotensin receptor type 1 antagonist losartan (10mg/kg) and the angiotensin-converting enzyme inhibitor captopril (3mg/kg). These were injected intraperitoneally 30min prior to blood pressure measurement by the tail-cuff method. We also studied the level of expression of preproET-1, ET-1 receptors, angiotensinogen and angiotensin receptors by RNA extraction from the heart and kidneys of these mice followed by reverse transcriptase (RT)-PCR. B2KO mice (HS) were hypertensive after 8 weeks compared with B2KO mice on normal diet (HS, 93.4±1.5mmHg, n = 7; NS, 61.4±2.7mmHg, n = 7). In the HS group, the mean arterial blood pressure was significantly reduced by BQ-123 (5mg/kg) to 61.9±1.8mmHg (n = 7), by BQ-788 (1mg/kg) to 58.8±2.6mmHg (n = 6), by losartan (10mg/kg) to 73.2±1.7mmHg (n = 8) and by captopril (3mg/kg) to 86.0±2.3mmHg (n = 8). The expression studied by RT-PCR did not show any difference (either in precursors or receptors expression) between hypertensive and normal mice. The four antagonists used seemed to reverse the hypertension. These results suggest that ET-1 and angiotensin-II are probably involved in the mechanism that leads to hypertension since the effect of these hormones is probably not compensated by kinins in B2KO mice. Further studies are necessary to understand the implication of the cross-talk between these hormones in the hypertensive state.

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