THE ROLE OF ENKEPHALINS IN BLOOD PRESSURE IN THE BRAIN

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

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

Hypertension ◽

10.1161/hyp.68.suppl_1.p152 ◽

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.

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Role of the Brain Renin-angiotensin System in Blood Pressure Regulation

Veterinary Research Communications ◽

10.1007/s11259-007-0062-z ◽

2007 ◽

Vol 31 (S1) ◽

pp. 343-346

Author(s):

M. V. Varoni ◽

D. Palomba ◽

M. P. Demontis ◽

S. Gianorso ◽

G. L. Pais ◽

...

Keyword(s):

Blood Pressure ◽

Renin Angiotensin System ◽

Blood Pressure Regulation ◽

Pressure Regulation ◽

Angiotensin System ◽

Renin Angiotensin ◽

The Brain

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Role of the brain melanocortins in blood pressure regulation

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2017.03.003 ◽

2017 ◽

Vol 1863 (10) ◽

pp. 2508-2514 ◽

Cited By ~ 11

Author(s):

Jussara M. do Carmo ◽

Alexandre A. da Silva ◽

Zhen Wang ◽

Taolin Fang ◽

Nicola Aberdein ◽

...

Keyword(s):

Blood Pressure ◽

Blood Pressure Regulation ◽

Pressure Regulation ◽

The Brain

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Endogenous opiate modulation of baroreflexes in normotensive and hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.5.h987 ◽

1988 ◽

Vol 255 (5) ◽

pp. H987-H991 ◽

Cited By ~ 1

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.

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Abstract 113: Glucose Metabolic Disorders in Aging-Associated Microglial NADPH Oxidase 2 Activation and Oxidative Damage of Cerebral Microvasculature and Neurons

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.113 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Li Geng ◽

Jian-Mei Li

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Blood Pressure ◽

Nadph Oxidase ◽

Metabolic Disorders ◽

Aging Brain ◽

Ros Generation ◽

Ros Production ◽

The Brain

Aging has been recognised to be a major risk factor for the development of cardiovascular and neurodegenerative diseases and growing evidence suggests a role for oxidative stress. A Nox2-containing NADPH oxidase has been reported to be a major source of reactive oxygen species (ROS) generation in the vascular system and in the brain. However, the role of Nox2 enzyme in aging-related metabolic disorders and vascular neurodegeneration remains unclear. In this study, we used age-matched wild-type (WT) and Nox2-deficient (Nox2 -/- ) mice on a C57BL/6 background at young (3-4 month) and aging (20-24 month) to investigate the role of Nox2 in aging-related oxidative stress, metabolic disorders and cerebral vascular dysfunction. There was an aging-related increase in blood pressure in WT mice (126 mmHg for young and 148 mmHg for aging) (P<0.05); however the blood pressure was well maintained without significant change in Nox2 -/- aging mice. Compared to young WT mice, WT aging mice had significantly high levels of fasting serum insulin and this was accompanied with delayed clearance of glucose (P<0.05) indicating insulin resistance. In contrast, there was no indication of insulin resistance for Nox2 -/- aging mice. We then examined aging-related brain oxidative stress. Compared to WT young mice, there were significant increases (2.7±0.7 folds) in the levels of ROS production by WT aging brain tissue homogenates as detected by lucigenin-chemiluminescence and DHE fluorescence. Increased ROS production in WT aging brain was accompanied by a significant increase (1.8±0.3 folds) in the Nox2 expression detected mainly in the microglial cells (labelled by Iba-1) and decreases in brain capillaries (labelled by CD31) (2.4±0.8 folds) and neurons (labelled by Neu-N) (2.9±0.5 folds) (all P<0.05). Knockout of Nox2 abolished aging-associated increases in brain ROS production and significantly reduced the aging-related pathophysiological changes in the brain. In conclusion, aging-associated metabolic disorders play a crucial role in aging-associated Nox2 activation and vascular neurodegeneration. Nox2-containing NADPH oxidase represents a valuable therapeutic target for oxidative stress-related brain microvascular damage and neurodegeneration.

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The Brain Melanocortin System, Sympathetic Control, and Obesity Hypertension

Physiology ◽

10.1152/physiol.00061.2013 ◽

2014 ◽

Vol 29 (3) ◽

pp. 196-202 ◽

Cited By ~ 14

Author(s):

Alexandre A. da Silva ◽

Jussara M. do Carmo ◽

Zhen Wang ◽

John E. Hall

Keyword(s):

Blood Pressure ◽

Essential Hypertension ◽

Sympathetic Activity ◽

Renal Diseases ◽

Melanocortin System ◽

Sympathetic Control ◽

Obesity Hypertension ◽

The Brain ◽

Cardiovascular Functions

Excess weight gain is the most significant, preventable cause of increased blood pressure (BP) in patients with primary (essential) hypertension and increases the risk for cardiovascular and renal diseases. In this review, we discuss the role of the brain melanocortin system in causing increased sympathetic activity in obesity and other forms of hypertension. In addition, we highlight potential mechanisms by which the brain melanocortin system modulates metabolic and cardiovascular functions.

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