Abstract WP309: Hypertensive Stimuli Promote Brain Inflammation and Cognitive Impairment in a Pressure-Dependent Manner

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Christopher G Sobey ◽  
Quynh Nhu Dinh ◽  
Antony Vinh ◽  
Grant R Drummond ◽  
Michael De Silva
Keyword(s):  
Blood Pressure ◽  
Cognitive Impairment ◽  
Angiotensin Ii ◽  
Recognition Memory ◽  
Immune Cell ◽  
Brain Inflammation ◽  
Dependent Manner ◽  
Ang Ii ◽  
Cell Numbers ◽  
The Brain

Background: Hypertension increases the risk for stroke and cognitive impairment, and is strongly associated with inflammation of the vasculature and kidneys. However, it is unclear whether there is inflammation and immune cell infiltration in the brain during hypertension. Aims: To test whether chronic infusion of angiotensin II causes brain inflammation and cognitive dysfunction, and whether its effects are blood pressure-dependent. Methods: Male C57Bl/6 mice were administered vehicle or angiotensin II (Ang II, 0.7 mg/kg/d s.c. ) via osmotic minipumps. A subset of mice also received hydralazine (50 mg/kg) in their drinking water after minipump implantation. We measured systolic blood pressure by tail cuff plethysmography, immune cell numbers using flow cytometry and recognition memory using the novel object recognition test. Results: Ang II infusion increased blood pressure and promoted accumulation of leukocytes in the brain, including neutrophils, monocytes, T cells and B cells, all of which were elevated by ~2.5-fold compared to vehicle-treated mice (n=6-8, P<0.05). Co-administration of hydralazine prevented the pressor response to Ang II and reduced neutrophil and monocyte infiltration (n=7-8, P<0.05), however, hydralazine had no effect on T or B cell numbers (n=7-8). Ang II impaired recognition memory and this was prevented by administration of hydralazine (n=11-12, P<0.05). Conclusions: Our data indicate that inflammation occurs in the brain during Ang II-dependent hypertension and this is associated with impaired recognition memory. Reducing blood pressure reversed these effects. Chronic brain inflammation may be a contributing factor to the increased stroke risk and cognitive impairment during hypertension and may be mitigated by blood pressure reduction.

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

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
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.

scholarly journals mTORC1 Signaling Contributes to Drinking But Not Blood Pressure Responses to Brain Angiotensin II

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3140-3148 ◽  
Author(s):  
Kenjiro Muta ◽  
Donald A. Morgan ◽  
Justin L. Grobe ◽  
Curt D. Sigmund ◽  
Kamal Rahmouni
Keyword(s):  
Angiotensin Ii ◽  
Water Intake ◽  
Drinking Behavior ◽  
Subfornical Organ ◽  
Dependent Manner ◽  
Ang Ii ◽  
Mtorc1 Signaling ◽  
Wide Range ◽  
The Brain

Mechanistic target of rapamycin complex 1 (mTORC1) is a molecular node that couples extracellular cues to a wide range of cellular events controlling various physiological processes. Here, we identified mTORC1 signaling as a critical mediator of angiotensin II (Ang II) action in the brain. In neuronal GT1–7 cells, we show that Ang II stimulates neuronal mTORC1 signaling in an Ang II type 1 receptor-dependent manner. In mice, a single intracerebroventricular (ICV) injection or chronic sc infusion of Ang II activated mTORC1 signaling in the subfornical organ, a critical brain region in cardiovascular control and fluid balance. Moreover, transgenic sRA mice with brain-specific overproduction of Ang II displayed increased mTORC1 signaling in the subfornical organ. To test the functional role of brain mTORC1 in mediating the action of Ang II, we examined the consequence of mTORC1 inhibition with rapamycin on Ang II-induced increase in water intake and arterial pressure. ICV pretreatment with rapamycin blocked ICV Ang II-mediated increases in the frequency, duration, and amount of water intake but did not interfere with the pressor response evoked by Ang II. In addition, ICV delivery of rapamycin significantly reduced polydipsia, but not hypertension, of sRA mice. These results demonstrate that mTORC1 is a novel downstream pathway of Ang II type 1 receptor signaling in the brain and selectively mediates the effect of Ang II on drinking behavior.

Abstract P127: Angiotensin II Priming Enhances Prostaglandin E2 Vasoconstrictor Effects

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Maria P Kraemer ◽  
Fred Lamb ◽  
Richard M Breyer
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Area Under The Curve ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Ang Ii ◽  
Concentration Dependent Manner ◽  
Femoral Arteries

Prostaglandins are key modulators of blood pressure and arterial tone. Prostaglandin E 2 (PGE 2 ), is a prostanoid that has vasodepressor effects; however, under certain circumstances PGE 2 can induce vasopressor responses. Recent reports demonstrated that sub-threshold concentrations of vasoconstrictors augment PGE 2 -mediated constriction in rat femoral arteries. However, whether angiotensin II (Ang II) could affect PGE 2 -mediated contraction is not known. Using a wire myograph, we demonstrated that PGE 2 had no significant effect on mouse femoral arterial rings at doses up to 1 μM. However, priming of arterial rings with 1 nM Ang II potentiated PGE 2 -evoked constriction in a concentration dependent manner (Area Under the Curve, AUC untreated 1.784 ± 0.353, AUC Ang II 23.27± 9.820, P<0.05). We tested femoral arteries from EP1, EP2, and EP3 receptor knockout mice. Only the EP3-/- arteries were unable to respond to PGE 2 after Ang II priming (figure below). Pretreatment of arterial rings with 1 μM losartan, an angiotensin receptor antagonist, blocked PGE 2 -induced constrictor effects primed with Ang II (% of KCl, Ang II 21.72 ± 5.296, Ang II + losartan 3.025 ± 1.046, n=3). We have determined that re-addition of extracellular Ca 2+ to a Ca 2+ -free artery restores PGE 2 -induced contractions (n=5) and that the Rho-kinase inhibitor Y-27632 blocks contraction (n=3). Taken together these data are consistent with angiotensin AT1 and prostaglandin EP3 receptors mediating a synergistic Rho-kinase-dependent contractile response. We are continuing to investigate the relationship between Ang II and PGE 2 to determine the physiological relevance this may have in modulating blood pressure.

Angiotensin II attenuates baroreflexes at nucleus tractus solitarius of rats

1986 ◽  
Vol 250 (2) ◽  
pp. R193-R198 ◽  
Author(s):  
R. Casto ◽  
M. I. Phillips
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Baroreflex Sensitivity ◽  
Nucleus Tractus Solitarius ◽  
Ang Ii ◽  
Spontaneously Hypertensive ◽  
Baroreceptor Reflexes ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
The Brain

Microinjection of angiotensin II (ANG II) into the nucleus tractus solitarius (NTS) has been shown to produce a dose-dependent increase in blood pressure and heart rate. We have tested the effect of subpressor infusions of ANG II (10 ng . kg-1 . min-1) in the NTS on reflex bradycardia after intravenous administration of the vasoconstrictor phenylephrine (1-12 micrograms) in normotensive urethan-anesthetized rats. ANG II within the brain is thought to contribute to the decreased baroreflex sensitivity in spontaneously hypertensive rats (SHR). The sensitivity of the baroreflex was significantly decreased by the infusion of ANG II (1.01 +/- 0.08) compared with control (2.41 +/- 0.51) in the normotensive animals. Baroreflex sensitivity was significantly decreased in SHR (0.40 +/- 0.21) compared with normotensive animals. We conclude that ANG II within the NTS can inhibit the function of baroreceptor reflexes in normotensive animals, suggesting that the endogenous peptide may perform an inhibitory role in the baroreflex arc, and this is further evidence that central ANG II is involved in blood pressure of SHR.

scholarly journals Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension

2015 ◽  
Vol 47 (10) ◽  
pp. 479-487 ◽  
Author(s):  
Xiao C. Li ◽  
Gary E. Shull ◽  
Elisa Miguel-Qin ◽  
Jia L. Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Glycogen Synthase ◽  
Proximal Tubules ◽  
Dependent Manner ◽  
Ang Ii ◽  
Lower Systolic Blood Pressure ◽  
Salt Wasting ◽  
Pressor Responses ◽  
Induced Hypertension

The renal mechanisms responsible for angiotensin II (ANG II)-induced hypertension remain incompletely understood. The present study tested the hypothesis that the Na+/H+ exchanger 3 (NHE3) is required for ANG II-induced hypertension in mice. Five groups of wild-type ( Nhe3 +/+) and Nhe3 −/− mice were treated with vehicle or high pressor doses of ANG II (1.5 mg/kg/day ip, via minipump for 2 wk, or 10 pmol/min iv for 30 min). Under basal conditions, Nhe3 −/− mice had significantly lower systolic blood pressure (SBP) and mean intra-arterial pressure (MAP) ( P < 0.01), 24 h urine ( P < 0.05), urinary Na+ ( P < 0.01) and urinary K+ excretion ( P < 0.01). In response to ANG II, SBP and MAP markedly increased in Nhe3 +/+ mice in a time-dependent manner, as expected ( P < 0.01). However, these acute and chronic pressor responses to ANG II were significantly attenuated in Nhe3 −/− mice ( P < 0.01). Losartan blocked ANG II-induced hypertension in Nhe3 +/+ mice but induced marked mortality in Nhe3 −/− mice. The attenuated pressor responses to ANG II in Nhe3 −/− mice were associated with marked compensatory humoral and renal responses to genetic loss of intestinal and renal NHE3. These include elevated basal plasma ANG II and aldosterone and kidney ANG II levels, salt wasting from the intestines, increased renal AQP1, Na+/HCO3−, and Na+/K+-ATPase expression, and increased PKCα, mitogen-activated protein kinases ERK1/2, and glycogen synthase kinase 3αβ signaling proteins in the proximal tubules ( P < 0.01). We concluded that NHE3 in proximal tubules of the kidney, along with NHE3 in intestines, is required for maintaining basal blood pressure as well as the full development of ANG II-induced hypertension.

Angiotensin II and bradykinin: interactions between two centrally active peptides

1983 ◽  
Vol 244 (2) ◽  
pp. R285-R291 ◽  
Author(s):  
R. E. Lewis ◽  
W. E. Hoffman ◽  
M. I. Phillips
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Pressor Response ◽  
Common Mechanism ◽  
Ang Ii ◽  
Active Peptides ◽  
Central Actions ◽  
Prostaglandin A2 ◽  
The Brain ◽  
Peptide Interaction

Two neuropeptides, bradykinin (BK) and angiotensin II (ANG II), produce an increase in blood pressure when injected into the brain ventricles. This study is an example of central peptide-peptide interaction and was carried out to determine if BK and ANG II share a common mechanism in the brain to control blood pressure and drinking in rats. Prior injection of saralasin [10 micrograms intraventricularly (ivt)] was found to enhance the pressor response to ivt BK (5 micrograms) by 44%. The same dose of saralasin attenuated the pressor response to ivt ANG II (200 ng) by 55%. 50 ng ANG II and 5 micrograms BK given together ivt did not significantly alter blood pressure or urine conductance compared to 50 ng ANG II alone. Drinking to ivt infusions of ANG II (14 ng/min) was significantly attenuated when combined with BK (0.7 micrograms or 2.8 micrograms/min). Pretreatment with 10 micrograms indomethacin ivt diminished the pressor response to 5 micrograms ivt BK. Prostaglandin E2 (1.4 micrograms/min), but not prostaglandin A2, inhibited drinking to 14 ng/min ivt infusions of ANG II. The results suggest that ANG II and BK share an interrelationship with respect to their central actions: ANG II inhibits the BK pressor response and BK acts to inhibit drinking induced by ANG II. Prostaglandins of the E series may mediate these central actions of bradykinins.

Cardiovascular actions of microinjections of angiotensin II in the brain stem of rats

1984 ◽  
Vol 246 (5) ◽  
pp. R811-R816 ◽  
Author(s):  
R. Casto ◽  
M. I. Phillips
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Angiotensin Ii ◽  
Brain Stem ◽  
Nucleus Tractus Solitarius ◽  
Area Postrema ◽  
Cardiovascular Response ◽  
Pressor Response ◽  
Ang Ii ◽  
The Brain

The blood pressure and heart rate responses to microinjection of angiotensin II (ANG II) into the brain stem of urethan-anesthetized rats were studied. Microinjection of ANG II into the area postrema (AP) resulted in significant elevation of blood pressure and significant reduction of heart rate. Microinjection into the region of the nucleus tractus solitarius (NTS) yielded a significant dose-dependent elevation in blood pressure and consistent increases in heart rate. The response to microinjection of ANG II into the region of the NTS was not due to leakage into the peripheral circulation, since intravenous administration of the ANG II antagonist, saralasin, did not attenuate the response. In fact, the cardiovascular response was increased after peripheral ANG II blockade, and the heart rate, which was consistently but not significantly elevated by NTS injection alone, was significantly elevated after saralasin pretreatment. Thermal ablation of the AP did not change the heart rate or the pressor response to microinjection of ANG II into the region of the NTS, indicating that the response was not mediated through the AP.

Abstract P011: Novel Roles Of Global, Intestinal, And Kidney Proximal Tubule Sodium And Hydrogen Exchanger 3 In Angiotensin Ii-induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Jia L Zhuo ◽  
Liang Zhang ◽  
Ana Leite ◽  
Xiao C Li
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Pressor Response ◽  
Dependent Manner ◽  
Ang Ii ◽  
Wild Type ◽  
Salt Wasting ◽  
Arterial Blood ◽  
Induced Hypertension

The present study used global ( Nhe3 -/- ), kidney-selective (tg Nhe3 -/- ), and proximal tubule-specific Na + /H + exchanger 3 (NHE3)-deficient mice (PT- Nhe3 -/- ) to test the hypothesis that NHE3 is required for the full development of angiotensin II (Ang II)-induced hypertension in mice. Four groups of adult male, age-matched wild-type (WT), global Nhe3 -/- , kidney-selective tg Nhe3 -/- and proximal tubule-specific Nhe3 -/- mice were infused with: a) saline; b) Ang II (10 pmol/min, i.v.); Ang II via an osmotic minipump for 2 weeks (1.5 mg/kg/day, i.p.); or treated with Ang II and losartan concurrently for 2 weeks (20 mg/kg/day, p.o.). Under basal conditions, global Nhe3 -/- , kidney-selective tg Nhe3 -/- and proximal tubule-specific Nhe3 -/- mice all showed significantly lower systolic, diastolic, and mean arterial pressure than wild-type mice (~15 ± 3 mmHg, P <0.01). The hypotensive phenotype in both global Nhe3 -/- and kidney-selective tg Nhe3 -/- mice was associated with abnormal intestinal structures, diarrhea, increased 24 h fecal Na + excretion, and salt wasting ( P <0.01). By contrast, there were no differences in intestinal structures and fecal Na + excretion between wild-type and PT- Nhe3 -/- mice. PT- Nhe3 -/- mice showed significant diuretic and natriuretic responses compared with wild-type mice ( P <0.01). Acute infusion of Ang II markedly increased arterial blood pressure in a time-dependent manner in wild-type mice, as expected ( P <0.01), but the pressure response was attenuated in global Nhe3 -/- , kidney-selective tg Nhe3 -/- , and PT- Nhe3 -/- mice ( P <0.01). Furthermore, the chronic pressor response to 2-week Ang II infusion was also significantly attenuated in Nhe3 -/- , tgNhe3 -/- , and PT- Nhe3 -/- mice, compared with wild-type mice ( P <0.01). Finally, concurrent treatment with losartan completely blocked the acute and chronic pressor responses to Ang II in wild-type, Nhe3 -/- , tg Nhe3 -/- , and PT- Nhe3 -/- mice (p<0.01). Taken together, these data support the proof of concept that NHE3 in the small intestines and the proximal tubules of the kidney is required for maintaining basal blood pressure homeostasis and for the development of Ang II-induced hypertension. Supported by NIH grants, 2R01DK102429-03A1, 1R56HL130988-01, and 2R01DK067299-10A1.

Central angiotensin II and PGE2 act independently to increase blood pressure in conscious sheep

1987 ◽  
Vol 252 (1) ◽  
pp. R73-R77
Author(s):  
B. A. Breuhaus ◽  
J. E. Chimoskey
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Renin Angiotensin System ◽  
Cyclooxygenase Inhibitors ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
Flunixin Meglumine ◽  
The Brain

Conscious adult female sheep chronically prepared with nonocclusive indwelling vascular and cerebroventricular catheters were used to determine whether centrally administered prostaglandin E2 (PGE2) increases blood pressure by activation of the brain renin angiotensin system or whether centrally administered angiotensin II (ANG II) increases blood pressure by stimulating prostaglandin synthesis in the brain. Intracerebroventricular (ivt) ANG II, 50 ng X kg-1 X min-1, increased arterial pressure 23 mmHg (P less than 0.01) 30 min after the start of infusion. Infusion of the ANG II antagonist [Sar1-Thr8]ANG II (sarthran), 1,000 ng X kg-1 X min-1 ivt, had no effect on arterial pressure when given by itself but reduced the ivt ANG II-induced pressor response to 5 mmHg (P less than 0.05) when the two peptides were infused at the same time. Intracerebroventricular infusion of sarthran did not alter the pressor responses to intracarotid (ic) PGE2 or to ivt PGE2. Blood pressure increased 21 mmHg (P less than 0.01) 30 min after the start of PGE2 infusion when PGE2 was given ic by itself, compared with 17 mmHg (P less than 0.01) when PGE2 was given ic at the same time as sarthran was given ivt. Blood pressure increased 14 mmHg (P less than 0.01) 30 min after the start of PGE2 infusion when PGE2 was given ivt by itself, compared with 16 mmHg (P less than 0.01) when PGE2 was given ivt at the same time as sarthran was given ivt. Pretreatment with the cyclooxygenase inhibitors indomethacin, 4 mg/kg sc, or flunixin meglumine, 3 mg/kg iv, did not alter the ivt ANG II-induced pressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

RAS in the Central Nervous System: Potential Role in Neuropsychiatric Disorders

2018 ◽  
Vol 25 (28) ◽  
pp. 3333-3352 ◽  
Author(s):  
Natalia Pessoa Rocha ◽  
Ana Cristina Simoes e Silva ◽  
Thiago Ruiz Rodrigues Prestes ◽  
Victor Feracin ◽  
Caroline Amaral Machado ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Neuropsychiatric Disorders ◽  
Extensive Literature ◽  
Ang Ii ◽  
Mas Receptor ◽  
The Central Nervous System ◽  
The Brain

Background: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. Objective: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. Method: We carried out an extensive literature search in PubMed central. Results: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Conclusion: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.

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