Role of AT2 receptor in the brain in regulation of blood pressure and water intake

2003 ◽  
Vol 284 (1) ◽  
pp. H116-H121 ◽  
Author(s):  
Zhen Li ◽  
Masaru Iwai ◽  
Lan Wu ◽  
Tetsuya Shiuchi ◽  
Toyohisa Jinno ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Water Intake ◽  
Pressor Response ◽  
Receptor Blocker ◽  
Dependent Manner ◽  
Ang Ii ◽  
Dose Dependent ◽  
Regulation Of Blood Pressure

The effects of intracerebroventricular (ICV) injection of angiotensin II (ANG II) on blood pressure and water intake were examined with the use of ANG II receptor-deficient mice. ICV injection of ANG II increased systolic blood pressure in a dose-dependent manner in wild-type (WT) mice and ANG type 2 AT2 receptor null (knockout) (AT2KO) mice; however, this increase was significantly greater in AT2KO mice than in WT mice. The pressor response to a central injection of ANG II in WT mice was inhibited by ICV preinjection of the selective AT1 receptor blocker valsartan but exaggerated by the AT2 receptor blocker PD-123319. ICV injection of ANG II also increased water intake. It was partly but significantly suppressed both in AT2KO and AT1aKO mice. Water intake in AT2/AT1aKO mice did not respond to ICV injection of ANG II. Both valsartan and PD-123319 partly inhibited water intake in WT mice. These results indicate an antagonistic action between central AT1a and AT2 receptors in the regulation of blood pressure, but they act synergistically in the regulation of water intake induced by ANG II.

Abstract P152: Aminopeptidase A in the Brain Exerts Cardiovascular Action via Degradation of Kallidin to Bradykinin

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Takuto Nakamura ◽  
Masanobu Yamazato ◽  
Yusuke Ohya
Keyword(s):  
Blood Pressure ◽  
Pressor Response ◽  
Cardiovascular Regulation ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Aminopeptidase A ◽  
Hoe 140 ◽  
Wistar Kyoto ◽  
The Brain

Objective: Aminopeptidase A (APA) degrades of various sympathomodulatory peptides such as angiotensin (Ang) II, cholecystkinin-8, neurokinin B and kallidin. APA activity is increased in the brain of hypertensive rats. A centrally acting APA inhibitor prodrug is currently under investigation in clinical trial for treatment of hypertension. In previous reports, a role of APA in the brain on cardiovascular regulation was researched focus on only renin-angiotensin system. We previously reported that intracerebroventricular(icv) administration of APA increased blood pressure and that this pressor response was partially blocked by angiotensin receptor blocker. In this study, we evaluated a role of APA on cardiovascular regulation focusing on peptides other than Ang II. Method: Eleven weeks old Wistar Kyoto rats were used. We icv administrated 800 ng/8 μL of APA after pretreatment of following drugs, i) 8μL of artificial cerebrospinal fluid (aCSF) as a control, ii) 80 nmol/8 μL of amastatin which is a non-specific aminopeptidase inhibitor, iii) 1 nmol/8 μL of HOE-140 which is a bradykinin receptor blocker to evaluate the involvement of degradation of kallidin to bradykinin by APA. Result: i) Icv administration of APA after pretreatment of aCSF increased blood pressure rapidly. Blood pressure reached a peak within 1 minute. The elevated blood pressure decreased gradually and reached baseline blood pressure in 10 minutes. A peak pressor response is 25.5±1.4 mmHg (n=5). ii) Icv pretreatment of amastatin or HOE-140 did not change the blood pressure. A peak pressor response induced by APA is 13.1±4.1 mmHg (n=6, p<0.05 vs aCSF). iii) Icv pretreatment of HOE-140 did not change the blood pressure. A peak pressor response induced by APA is 21.2±1.8 mmHg (n=4, p<0.05 vs aCSF). Conclusion: 1) Icv administration of APA increased blood pressure by APA enzymatic activity. 2) Cardiovascular regulation of APA in the brain is due to not only degradation of Ang II to Ang III but also degradation of kallidin to bradykinin. Clinical implication: We think inhibition of APA in the brain may be a unique therapeutic target which affects several cardiovascular peptides in the brain.

Role of paraventricular nucleus in control of blood pressure and drinking in rats

1992 ◽  
Vol 262 (6) ◽  
pp. F1068-F1075 ◽  
Author(s):  
L. L. Jensen ◽  
J. W. Harding ◽  
J. W. Wright
Keyword(s):  
Blood Pressure ◽  
Paraventricular Nucleus ◽  
Critical Role ◽  
Systemic Blood Pressure ◽  
Dependent Manner ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Systemic Blood ◽  
Dose Dependent

The present investigation examined the abilities of angiotensin (ANG) II and III to produce increases in blood pressure and drinking when microinfused into the paraventricular nucleus (PVN) of the hypothalamus of the Sprague-Dawley rat. Dose-dependent elevations in systemic blood pressure and heart rate were measured to both ANG II and III in the anesthetized rat, with ANG II more potent than ANG III at the two highest doses examined. Pretreatment with the specific ANG receptor antagonist [Sar1,Thr8]ANG II (sarthran), blocked subsequent ANG II- and III-induced elevations in blood pressure, suggesting that these responses were dependent on the activation of ANG receptors. A similar analysis in awake rats yielded nearly equivalent results. A final experiment demonstrated that microinfusions of ANG II and III into the PVN produced drinking in a dose-dependent manner, with greater consumption to ANG II than ANG III. Again, sarthran was found to block the dipsogenic response. Histological examination revealed that the location of the injection site was linked to the character of the ANG-dependent response. These data suggest that the PVN may play a critical role in mediating central ANG effects on body water homeostasis and blood pressure regulation. Furthermore, it appears that subnuclei of the PVN may participate differentially in ANG-mediated actions.

Role of the At 2 Receptor in the Cardioprotective Effect of At 1 Antagonist in Mice with Chronic Heart Failure Induced by Coronary Ligation

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 704-704
Author(s):  
Jiang Xu ◽  
Oscar A Carretero ◽  
Yun-He Liu ◽  
Edward G Shesely ◽  
Fang Yang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Cardioprotective Effect ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Coronary Ligation ◽  
Regulation Of Blood Pressure

P63 Angiotensin II (Ang II) acts mainly on two receptor subtypes: type 1 (AT 1 ) and type 2 (AT 2 ). Most of the known biological actions of Ang II are mediated via AT 1 receptors; however, the role of the AT 2 receptor is less well defined. We hypothesized that blockade of AT 1 receptors increases circulating Ang II levels, which in turn activates the AT 2 receptor and induces cardioprotection. In mice which lack AT 2 receptors, the effect of an AT 1 antagonist (AT 1 -ant) would be diminished or absent. AT 2 receptor knockout mice (-/-) and their wild-type littermates (+/+) were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. One month after MI, each strain of mice received either vehicle or AT 1 -ant (valsartan, 50 mg/kg/day in drinking water) for 3 months. Systolic blood pressure (SBP) was measured weekly and echocardiography performed once a month. Basal SBP and cardiac function did not differ between +/+ and -/-. Three months after MI, SBP and cardiac function changed similarly in both strains receiving vehicle. Valsartan significantly increased EF and decreased LVDd and mass and these effects were diminished in -/- (table). Our results suggest that under basal conditions, the AT 2 receptor may not play an important role in regulation of blood pressure and cardiac function; however, it does appear to be an important component in the cardioprotective effect of AT 1 -ant.

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 ◽  
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.

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

1993 ◽  
Vol 265 (3) ◽  
pp. R591-R595 ◽  
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.

scholarly journals Excess of Aminopeptidase A in the Brain Elevates Blood Pressure via the Angiotensin II Type 1 and Bradykinin B2 Receptors without Dipsogenic Effect

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Takuto Nakamura ◽  
Masanobu Yamazato ◽  
Akio Ishida ◽  
Yusuke Ohya
Keyword(s):  
Blood Pressure ◽  
Pressor Response ◽  
Drinking Behavior ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Aminopeptidase A ◽  
Hoe 140 ◽  
B2 Receptors ◽  
The Brain

Aminopeptidase A (APA) cleaves angiotensin (Ang) II, kallidin, and other related peptides. In the brain, it activates the renin angiotensin system and causes hypertension. Limited data are available on the dipsogenic effect of APA and pressor effect of degraded peptides of APA such as bradykinin. Wistar-Kyoto rats received intracerebroventricular (icv) APA in a conscious, unrestrained state after pretreatment with (i) vehicle, (ii) 80 μg of telmisartan, an Ang II type-1 (AT1) receptor blocker, (iii) 800 nmol of amastatin, an aminopeptidase inhibitor, and (iv) 1 nmol of HOE-140, a bradykinin B2 receptor blocker. Icv administration of 400 and 800 ng of APA increased blood pressure by 12.6 ± 3.0 and 19.0 ± 3.1 mmHg, respectively. APA did not evoke drinking behavior. Pressor response to APA was attenuated on pretreatment with telmisartan (vehicle: 22.1 ± 2.2 mmHg versus telmisartan: 10.4 ± 3.2 mmHg). Pressor response to APA was also attenuated with amastatin and HOE-140 (vehicle: 26.5 ± 1.1 mmHg, amastatin: 14.4 ± 4.2 mmHg, HOE-140: 16.4 ± 2.2 mmHg). In conclusion, APA increase in the brain evokes a pressor response via enzymatic activity without dipsogenic effect. AT1 receptors and B2 receptors in the brain may contribute to the APA-induced pressor response.

Role of endogenous angiotensin II on sympathetic reflexes in conscious rabbits

1997 ◽  
Vol 272 (6) ◽  
pp. R1816-R1825 ◽  
Author(s):  
R. D. Bendle ◽  
S. C. Malpas ◽  
G. A. Head
Keyword(s):  
Angiotensin Ii ◽  
Pressor Response ◽  
Ang Ii ◽  
At1 Antagonist ◽  
Before And After ◽  
Sympathetic Reflexes ◽  
Conscious Rabbits ◽  
Dose Dependent ◽  
Renal Sympathetic

In the present study we sought to determine the contribution of endogenous brain stem angiotensin to renal sympathetic reflexes in conscious rabbits. Initial studies determined the subtype of receptor involved in the pressor response to angiotensin II (ANG II) administration into the fourth ventricle (4V). The AT1 antagonist losartan (0.001-10 micrograms 4V) had no effect on blood pressure alone but caused a dose-dependent blockade of the pressor effect of ANG II, with complete blockade produced by 10 micrograms, an effect that lasted for at least 3 h. The AT2 antagonist PD-123319 (0.1-1,000 micrograms) and vehicle had no effect on the ANG II pressor response. The effect of losartan (10 micrograms) on the baroreceptor, chemoreceptor, and trigeminal reflexes was examined in eight rabbits that had been implanted with 4V catheters and an electrode for recording renal sympathetic nerve activity (RSNA) 1 wk earlier. Baroreflex assessments were made during normoxia and two conditions of hypoxia (10% O2 and 10% O2 + 3% CO2) before and after 10 micrograms losartan or vehicle, on separate experimental days. During normoxia and hypoxia+CO2 losartan increased resting RSNA, the range, and upper plateau of the RSNA-MAP baroreflex curves. By contrast the marked increase in RSNA due to activation of trigeminal afferents was not affected by losartan. In conclusion the effect of losartan to increase RSNA activity in conscious rabbits, particularly during hypoxia and baroreceptor unloading, suggests that endogenous ANG II via AT1 receptors normally inhibits renal sympathetic baroreceptor and chemoreceptor reflexes.

scholarly journals Expression of Type 2 Iodothyronine Deiodinase in Corticotropin-Secreting Mouse Pituitary Tumor Cells Is Stimulated by Glucocorticoid and Corticotropin-Releasing Hormone

Endocrinology ◽  
2003 ◽  
Vol 144 (10) ◽  
pp. 4459-4465 ◽  
Author(s):  
Osamu Araki ◽  
Tadashi Morimura ◽  
Takayuki Ogiwara ◽  
Haruo Mizuma ◽  
Masatomo Mori ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pituitary Tumor ◽  
Northern Analysis ◽  
Dependent Manner ◽  
Iodothyronine Deiodinase ◽  
Mouse Pituitary ◽  
Dose Dependent ◽  
Menten Constant

We identified the presence of iodothyronine deiodinase in AtT-20 mouse pituitary tumor cells that secrete corticotropin. Iodothyronine deiodinating activity in AtT-20 cells fulfills all the characteristics of type 2 iodothyronine deiodinase (D2), including the inhibition by thyroid hormones, the insensitivity to inhibition by 6-propyl-2-thiouracil, and the low Michaelis-Menten constant value for T4. Northern analysis using mouse D2 cRNA probe demonstrated the hybridization signal of approximately 7.0 kb in size in AtT-20 cells. D2 activity and D2 mRNA were stimulated by glucocorticoid in a dose-dependent manner but were not stimulated by testosterone or β-estradiol. D2 expression was stimulated by (Bu)2cAMP, and CRH in a dose-dependent manner in the presence of dexamethasone. These results suggest the previously unrecognized role of local thyroid hormone activation by D2 in the regulation of pituitary corticotrophs.

Antithrombotic role of nitric oxide in rats under physiological conditions

2004 ◽  
Vol 91 (01) ◽  
pp. 71-75 ◽  
Author(s):  
Mariko Okudaira ◽  
Yasuo Ontachi ◽  
Tomoe Mizutani ◽  
Mika Omote ◽  
Tomotaka Yoshida ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Hepatic Dysfunction ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Fibrin Deposition ◽  
Physiological Conditions ◽  
Synthase Inhibitor ◽  
Dose Dependent

SummaryAlthough sepsis-induced release of nitric oxide (NO) is known to have an antithrombotic effect, it is unknown if NO exerts this same effect under physiological conditions. We have therefore attempted to determine whether or not NO protects against thrombus formation in normal Wistar rats injected with various amounts (0.8, 4.0, 20.0 and 100mg/kg/4hr) of L-NAME (N (omega)-nitro-l-arginine methyl ester), an NO synthase inhibitor, via the tail vein. Plasma levels of D-dimer fragments of fibrin were significantly increased in rats receiving L-NAME (0.21±0.04, 0.22±0.05, 0.26±0.07, 0.59±0.17µg/mL, means±SE; p<0.05, 0.05, 0.05, 0.01: L-NAME 0.8, 4, 20, 100, respectively, compared with control levels: <0.06 µg/mL), and thrombin-antithrombin complex (TAT) levels were significantly increased in rats receiving 20mg/kg/4hr or greater doses of L-NAME (4.5±1.1, 4.7±1.4, 18.7±4.9, 42.5±4.0ng/mL, NS, NS, p<0.05, 0.01, respectively, compared with control levels: 3.8±1.2 ng/mL). Glomerular fibrin deposition was increased in a dose-dependent manner in rats receiving L-NAME (6.8±1.5, 13.9±1.6, 32.4±2.6, 49.2±5.2%, p<0.05, 0.05, 0.01, 0.01, respectively, compared with control levels: 0.0±0.0%). Renal dysfunction and hepatic dysfunction were observed in rats receiving 20mg/kg/4hr or greater, or 100mg/kg/4hr, doses of L-NAME, respectively. Mean blood pressure was also elevated in rats receiving L-NAME in a dose-dependent manner. These findings suggest that NO, in addition to regulating blood pressure, is involved in prevention of thrombus formation under physiological circumstances.

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