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

Hypertension ◽  
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.

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.

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.

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.

scholarly journals Renal Vascular Response to Angiotensin II Administration in Two Kidneys-One Clip Hypertensive Rats Treated with High Dose of Estradiol: The Role of Mas Receptor

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Samira Choopani ◽  
Mehdi Nematbakhsh
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Ovariectomized Rats ◽  
Ang Ii ◽  
Vascular Response ◽  
Hypertensive Rats ◽  
Vascular Responses ◽  
Mas Receptor ◽  
Renal Vascular

Backgrounds. High blood pressure is one of the most important causes of death around the world. The renin-angiotensin system (RAS) and estradiol are two important items that regulate arterial blood pressure in women. However, hypertension, RAS, and sex hormone estradiol may influence renal vascular responses. This study was designed to determine the role of Mas receptor (MasR) on renal vascular response to angiotensin II (Ang II) administration in two kidneys-one clip (2K1C) hypertensive rats treated with estradiol. Method. The ovariectomized rats were subjected to 2K1C or non-2K1C and simultaneously treated with estradiol (500 μg/kg/weekly) or placebo for a period of 4 weeks. Subsequently, under anesthesia, renal vascular responses to graded doses of Ang II administration with MasR blockade (A779) or its vehicle were determined. Results. A779 or its vehicle did not alter mean arterial pressure (MAP), renal perfusion pressure (RPP), and renal blood flow (RBF). However, in non-2K1C rats, Ang II infusion decreased RBF and increased renal vascular resistance (RVR) responses in a dose-related manner ( P treat < 0.0001 ). The greatest responses were found in ovariectomized estradiol-treated rats that received A779 ( P group < 0.05 ) in non-2K1C rats. Such findings were not detected in 2K1C hypertensive rats. For example, in estradiol-treated rats that received A779, at 1000 ng/kg/min of Ang II infusion, RBF reduced from 1.6 ± 0.2 to 0.89 ± 0.19  ml/min in non-2K1C rats, and it reduced from 1.6 ± 0.2 to 1.2 ± 0.2  ml/min in 2K1C rats. Conclusion. Hypertension induced by 2K1C may attenuate the role of A779 and estradiol in renal vascular responses to Ang II infusion. Perhaps, this response can be explained by the reduction of Ang II type 1 receptor (AT1R) expression in the 2K1C hypertensive rats.

Angiotensin, Thirst, and Sodium Appetite

1998 ◽  
Vol 78 (3) ◽  
pp. 583-686 ◽  
Author(s):  
J. T. FITZSIMONS
Keyword(s):  
Blood Pressure ◽  
Brain Stem ◽  
Blood Pressure Control ◽  
Drinking Behavior ◽  
Pressure Control ◽  
Ang Ii ◽  
Sodium Appetite ◽  
Angiotensin Peptides ◽  
Body Fluid Homeostasis ◽  
The Brain

Fitzsimons, J. T. Angiotensin, Thirst, and Sodium Appetite. Physiol. Rev. 78: 583–686, 1998. — Angiotensin (ANG) II is a powerful and phylogenetically widespread stimulus to thirst and sodium appetite. When it is injected directly into sensitive areas of the brain, it causes an immediate increase in water intake followed by a slower increase in NaCl intake. Drinking is vigorous, highly motivated, and rapidly completed. The amounts of water taken within 15 min or so of injection can exceed what the animal would spontaneously drink in the course of its normal activities over 24 h. The increase in NaCl intake is slower in onset, more persistent, and affected by experience. Increases in circulating ANG II have similar effects on drinking, although these may be partly obscured by accompanying rises in blood pressure. The circumventricular organs, median preoptic nucleus, and tissue surrounding the anteroventral third ventricle in the lamina terminalis (AV3V region) provide the neuroanatomic focus for thirst, sodium appetite, and cardiovascular control, making extensive connections with the hypothalamus, limbic system, and brain stem. The AV3V region is well provided with angiotensinergic nerve endings and angiotensin AT1 receptors, the receptor type responsible for acute responses to ANG II, and it responds vigorously to the dipsogenic action of ANG II. The nucleus tractus solitarius and other structures in the brain stem form part of a negative-feedback system for blood volume control, responding to baroreceptor and volume receptor information from the circulation and sending ascending noradrenergic and other projections to the AV3V region. The subfornical organ, organum vasculosum of the lamina terminalis and area postrema contain ANG II-sensitive receptors that allow circulating ANG II to interact with central nervous structures involved in hypovolemic thirst and sodium appetite and blood pressure control. Angiotensin peptides generated inside the blood-brain barrier may act as conventional neurotransmitters or, in view of the many instances of anatomic separation between sites of production and receptors, they may act as paracrine agents at a distance from their point of release. An attractive speculation is that some are responsible for long-term changes in neuronal organization, especially of sodium appetite. Anatomic mismatches between sites of production and receptors are less evident in limbic and brain stem structures responsible for body fluid homeostasis and blood pressure control. Limbic structures are rich in other neuroactive peptides, some of which have powerful effects on drinking, and they and many of the classical nonpeptide neurotransmitters may interact with ANG II to augment or inhibit drinking behavior. Because ANG II immunoreactivity and binding are so widely distributed in the central nervous system, brain ANG II is unlikely to have a role as circumscribed as that of circulating ANG II. Angiotensin peptides generated from brain precursors may also be involved in functions that have little immediate effect on body fluid homeostasis and blood pressure control, such as cell differentiation, regeneration and remodeling, or learning and memory. Analysis of the mechanisms of increased drinking caused by drugs and experimental procedures that activate the renal renin-angiotensin system, and clinical conditions in which renal renin secretion is increased, have provided evidence that endogenously released renal renin can generate enough circulating ANG II to stimulate drinking. But it is also certain that other mechanisms of thirst and sodium appetite still operate when the effects of circulating ANG II are blocked or absent, although it is not known whether this is also true for angiotensin peptides formed in the brain. Whether ANG II should be regarded primarily as a hormone released in hypovolemia helping to defend the blood volume, a neurotransmitter or paracrine agent with a privileged role in the neural pathways for thirst and sodium appetite of all kinds, a neural organizer especially in sodium appetite, or all of these, remains uncertain. ANG II-induced drinking behavior serves as a model of how other complex behaviors involving neural and peptide inputs might be organized.

Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure

2000 ◽  
Vol 28 (4) ◽  
pp. 435-440 ◽  
Author(s):  
A. Reaux ◽  
X. Iturrioz ◽  
G. Vazeux ◽  
M.-C. Fournie-Zaluski ◽  
C. David ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Renin Angiotensin System ◽  
Central Control ◽  
Angiotensin System ◽  
Arterial Blood ◽  
Angiotensin Iii ◽  
Aminopeptidase A ◽  
The Brain

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental animal models. We have recently reported that, in the murine brain RAS, angiotensin II (AngII) is converted by aminopeptidase A (APA) into angiotensin III (AngIII), which is itself degraded by aminopeptidase N (APN), both peptides being equipotent to increase vasopressin release and arterial blood pressure when injected by the intracerebroventricular (i.c.v.) route. Because AngII is converted in vivo into AngIII, the exact nature of the active peptide is not precisely known. To delineate their respective roles in the central control of cardiovascular functions, specific and selective APA and APN inhibitors are needed to block the metabolic pathways of AngII and AngIII respectively. In the absence of such compounds for APA, we first explored the organization of the APA active site by site-directed mutagenesis. This led us to propose a molecular mechanism of action for APA similar to that proposed for the bacterial enzyme thermolysin deduced from X-ray diffraction studies. Secondly, we developed a specific and selective APA inhibitor, compound EC33 [(S)-3-amino-4-mercaptobutylsulphonic acid], as well as a potent and selective APN inhibitor, PC18 (2-amino-4-methylsulphonylbutane thiol). With these new tools we examined the respective roles of AngII and AngIII in the central control of arterial blood pressure. A central blockade of APA with the APA inhibitor EC33 suppressed the pressor effect of exogenous AngII, suggesting that brain AngII must be converted into AngIII to increase arterial blood pressure. Furthermore, EC33, injected alone i.c.v. but not intravenously, caused a dose-dependent decrease in arterial blood pressure by blocking the formation of brain AngIII but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor PC 18 administered alone via the i.c.v. route increased arterial blood pressure. This pressor response was blocked by prior treatment with the angiotensin type 1 receptor antagonist losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in arterial blood pressure increase through an interaction with angiotensin type 1 receptors. These results demonstrate that AngIII is a major effector peptide of the brain RAS, exerting a tonic stimulatory control over arterial blood pressure. Thus APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors, crossing the blood-brain barrier, as central anti-hypertensive agents.

Abstract 558: Role of Angiotensin Converting Enzyme 2/angiotensin (1-7)/mas Axis in the Hypotensive Effect of Azilsartan

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Jun Iwanami ◽  
Masaki Mogi ◽  
Kana Tsukuda ◽  
Xiao-Li Wang ◽  
Kousei Ohshima ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drug Administration ◽  
Group Treatment ◽  
Mrna Level ◽  
Weight Ratio ◽  
Hypotensive Effect ◽  
Ang Ii ◽  
Converting Enzyme

Objective: The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang (1-7)/Mas axis against the ACE/Ang II/ Ang II type 1 (AT 1 ) receptor axis in blood pressure control has been highlighted. We examined the possibility that this axis might be involved in the anti-hypertensive effect of newly developed Ang II type 1 (AT 1 ) receptor blocker (ARB), azilsartan, in comparison with olmesartan. Methods: Human renin (hRN) and human angiotensinogen (hANG) double transgenic mice (hRN/hANG-Tg) were used. Ten-week-old male hRN/hANG-Tg mice were administrated control chow or three different doses (1, 5 and 10mg/kg/day) of ARBs, azilsartan or olmesartan in chow for 4 weeks. Blood pressure was analyzed by radio telemetry method before drug administration and every two weeks after medication. Four weeks after drug administration, expression of ACE2 mRNA level was assessed by real time RT-PCR method. Results: Blood pressure was significantly higher in hRN/hANG-Tg mice compared with that in wild type (WT) mice. Treatment with all doses of azilsartan decreased blood pressure to the level of WT mice. Treatment with olmesartan (1 mg/kg/day) decreased blood pressure; however, this decrease was weaker than that with azilsartan at the same dose. Olmesartan (5 and 10 mg/kg/day) decreased blood pressure to the WT mice level; however, the reduction of blood pressure in the night-time was stronger in azilsartan group. Expression of ACE2 mRNA was decreased in heart and kidney of hRN/hANG-Tg mice compared with WT mice. This decrease in ACE2 mRNA expression was attenuated by administration of azilsartan, but not by olmesartan treatment. The ratio of heart to body weight ratio was decreased in all azilsartan-treated groups, but this decrease was observed only in 10 mg/kg/day of olmesartan-treated group. Treatment with azilsartan even at lower dose increased the urinary excretion of Na. Conclusion: These results suggested that hypotensive effect of azilsartan may involve the activation of ACE2/Ang(1-7)/Mas axis with AT 1 receptor blockade. Further investigation will reveal the pathophysiological role of ACE2/Ang(1-7)/Mas axis in blood ptessure control and contribute to discuss further the possible drug effect of ARBs beyond class effect.

Endogenous opiate modulation of baroreflexes in normotensive and hypertensive rats

1988 ◽  
Vol 255 (5) ◽  
pp. H987-H991 ◽  
Author(s):  
J. E. Szilagyi
Keyword(s):  
Blood Pressure ◽  
Renovascular Hypertension ◽  
Baroreflex Sensitivity ◽  
Baroreceptor Reflex ◽  
Hypertensive Rats ◽  
Endogenous Opiates ◽  
Endogenous Opiate ◽  
The Brain ◽  
Naloxone Treatment

It is evident that hypertension is associated with elevated endogenous opiates. This study was designed to examine the role of endogenous opiates in the development and/or maintenance of two-kidney renovascular hypertension and in baroreceptor reflex function in conscious hypertensive rats. Naloxone administration during the onset of hypertension significantly attenuated the rise in blood pressure. After one week, systolic blood pressure in naloxone-treated rats was 27 mmHg lower than in 0.9% NaCl-treated hypertensive rats. Acute naloxone infusions in chronic hypertensive animals also significantly lowered blood pressure (-10%) and heart rate (-26%). Baroreceptor function was significantly enhanced in both normotensive (+135%) and hypertensive (+207%) rats after administration of naloxone. Furthermore, naloxone treatment also caused the baroreflex response to shift from the higher reset state toward that seen in normotensive counterparts. The inability of naloxone methyl bromide to alter baroreflex sensitivity indicates that the site(s) of action of opiates resides in the brain. These data support a role for opiates in the development and/or maintenance of renovascular hypertension, which may be related to alterations in baroreceptor reflex function.

Abstract 25: Prorenin Elevates Blood Pressure via the (Pro)renin Receptor: Who Needs Renin When You Have Prorenin in the Brain

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Yumei Feng ◽  
Wencheng Li ◽  
Hua Peng ◽  
Atsuhiro Ichihara
Keyword(s):  
Blood Pressure ◽  
Pressor Response ◽  
Ang Ii ◽  
Key Factors ◽  
Brain Neuron ◽  
Neurogenic Hypertension ◽  
Salt Hypertension ◽  
The Brain

Growing evidence supports that the brain renin-angiotensin (Ang) system (RAS) plays an important role in blood pressure (BP) regulation and hypertension. This concept has been perplexed by extremely low renin activity in the brain. We recently reported the presence of prorenin in the mouse brain at a level of 10-fold higher than that of renin. In addition, we and others have identified the localization of the (pro)renin receptor (PRR) in various brain nuclei involved in BP regulation. The binding of prorenin to PRR leads to Ang II formation in vitro. Our hypothesis: Brain prorenin binding to PRR mediates Ang II formation, leading to an increase in BP. To test this, neuron-specific PRR knockout mice (Nefh-PRR) and wildtype (WT) littermates (N=5/group) were each implanted with a telemetric probe for BP recording and an intracerebroventricular (ICV) cannula for infusion of mouse prorenin (100ng/ul), mouse renin (100ng/ul), or Ang II type 1 receptor (AT1R) blocker (losartan, 10ug/ul) at 0.3ul/minute for 10 minutes. Mouse prorenin infusion increased the BP (mmHg) in WT mice (ΔMAP: 41 ± 5); however, the prorenin-induced pressor response was abolished in Nefh-PRR mice (ΔMAP: 5 ± 1). Infusion of mouse renin similarly increased BP in Nefh-PRR (ΔMAP: 27 ± 2) and WT (ΔMAP: 31 ± 5) mice. The pressor response induced by prorenin or renin was completely blocked by the infusion of losartan. The data suggests that ICV prorenin via PRR mediates Ang II-dependent pressor response in WT mice. To determine whether PRR contributes to the development of brain RAS-dependent hypertension, Nefh-PRR and WT littermates (N=8/group) were treated with 50mg of deoxycorticosterone acetate (DOCA) subcutaneously, plus 0.9% NaCl drinking water for 21 days. The baseline BP was similar between Nefh-PRR (101 ± 2) and WT (101 ± 3) mice. BP was increased in WT mice (132 ± 6) by DOCA-salt treatment, while Nefh-PRR mice remained normotensive (108 ± 3). In summary, prorenin via PRR mediates AngII/AT1R-dependent pressor response in the brain. Neuron-specific PRR deletion attenuates the development of DOCA-salt hypertension likely due to the lack of Ang II/AT1R activation. We conclude that prorenin/PRR may be the key factors to initiate the brain RAS and play an essential role in neurogenic hypertension.

Abstract 43: Non-Canonical AT1R/b-Arrestin2 Activation In Brain As A Regulator Of Fluid Homeostasis And Blood Pressure

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Natalia M Mathieu ◽  
Pablo Nakagawa ◽  
Daniel Brozoski ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Metabolic Regulation ◽  
Pressor Response ◽  
Drinking Behavior ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Genetic Ablation ◽  
Fluid Homeostasis ◽  
Saline Preference ◽  
The Brain

The brain renin angiotensin system (RAS) is known for its role in cardiovascular and metabolic regulation. Angiotensin II (Ang II) is the major active product of the RAS, exerting most of its physiological effects through the angiotensin type-1 receptor (AT 1 R). Canonical or G-protein-mediated signaling of the AT 1 R within the brain has long been known to induce a dipsogenic and pressor response upon Ang II stimulation. Non-canonical or β-Arrestin mediated signaling is thought to counterbalance the detrimental effects of canonical signaling. However, the non-canonical AT 1 R/β-Arrestin pathway within the brain is understudied. Therefore, it is hypothesized that β-Arrestin activation contributes to fluid homeostasis and blood pressure (BP) regulation. Global β-Arrestin1 ( Arrb 1) and β-Arrestin2 ( Arrb 2) knockout (KO) mice were employed to evaluate drinking behavior and BP with and without deoxycorticosterone acetate (DOCA). Age- and sex-matched C57BL/6J mice served as controls. Mice were subjected to the two-bottle choice paradigm, in which the animals were presented with two bottles, one containing water and one containing 0.15M saline. In the absence of DOCA, mice lacking β-Arrestin2 had increased saline intake when compared to β-Arrestin1-KO and wildtype (WT=2.2±0.2 and Arrb 1-KO=2±0.4 vs Arrb 2-KO=5±0.7 mL/day; p<0.001; n=13, 11 and 9, respectively). This resulted in a saline preference, which means mice preferred saline over water by more than 50% by volume. In the presence of DOCA, mice lacking β-Arrestin2 had increased saline intake when compared to β-Arrestin1-KO and wildtype (WT=10.6±1.2 and Arrb 1-KO=6.5±0.8 vs Arrb 2-KO=16.6±2 mL/day; p<0.001; n=13, 11 and 9, respectively). However, these mice did not develop a saline preference. Preliminarily, β-Arrestin2-KO mice exhibited higher BP when compared to WT at baseline (WT=108±5 vs Arrb 2-KO=124±6 mmHg; n=2), which was exacerbated in response to DOCA (WT=122±6 vs Arrb 2-KO=140±5 mmHg; n=2). These findings suggest that β-Arrestin2 might counterbalance effects of canonical activation of the AT 1 R through G proteins. Overall, β-Arrestin2 appears to protect against cardiovascular diseases since the genetic ablation of β-Arrestin2 resulted in an increase in saline intake and exacerbated BP.

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