EFFECT OF SEQUENTIAL NEPHRON BLOCKING IN COMPARISON WITH THE DOUBLE BLOCKADE OF THE RENIN- ANGIOTENSIN SYSTEM + BISOPROLOL ON CENTRAL SYSTOLIC BLOOD PRESSURE AND ARTERIAL STIFFNESS

The aim of the present study was to compare the antihypertrophic effects of blockade of the renin–angiotensin system (RAS), vasopeptidase inhibition and calcium channel antagonism on cardiac and vascular hypertrophy in diabetic spontaneously hypertensive rats (SHR). SHR with streptozotocin-induced diabetes were treated with one of the following therapies for 32 weeks: the angiotensin-converting enzyme (ACE) inhibitor captopril (100mg/kg); the angiotensin AT1 receptor antagonist valsartan (30mg/kg); a combination of captopril with valsartan; the vasopeptidase inhibitor mixanpril (100mg/kg); or the calcium channel antagonist amlodipine (6mg/kg). Systolic blood pressure and cardiac and mesenteric artery hypertrophy were assessed. Mean systolic blood pressure in diabetic SHR (200±5mmHg) was reduced by captopril (162±5mmHg), valsartan (173±5mmHg), mixanpril (176±2mmHg) and amlodipine (159±4mmHg), and was further reduced by the combination of captopril with valsartan (131±5mmHg). Captopril, valsartan and mixanpril reduced heart and left ventricle weights by approx. 10%. The combination of captopril and valsartan further reduced heart weight (-24%) and left ventricular weight (-29%). Amlodipine did not affect cardiac hypertrophy. Only mixanpril and the combination of captopril and valsartan significantly reduced mesenteric weight. The mesenteric wall/lumen ratio was reduced by all drugs, and to a greater extent by the combination of captopril and valsartan. We conclude that optimizing the blockade of vasoconstrictive pathways such as the RAS, particularly with the combination of ACE inhibition and AT1 receptor antagonism, is associated with antitrophic effects in the context of diabetes and hypertension. In contrast, calcium channel blockade, despite similar effects on blood pressure, confers less antitrophic effects in the diabetic heart and blood vessels.

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Increased (pro)renin receptor expression in the subfornical organ of hypertensive humans

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00616.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. H796-H804 ◽

Cited By ~ 5

Author(s):

Silvana G. Cooper ◽

Darshan P. Trivedi ◽

Rieko Yamamoto ◽

Caleb J. Worker ◽

Cheng-Yuan Feng ◽

...

Keyword(s):

Blood Pressure ◽

Animal Models ◽

Systolic Blood Pressure ◽

Renin Angiotensin System ◽

Subfornical Organ ◽

Antihypertensive Drug Therapy ◽

Angiotensin System ◽

Human Hypertension ◽

Renin Angiotensin ◽

The Brain

The central nervous system plays an important role in essential hypertension in humans and in animal models of hypertension through modulation of sympathetic activity and Na+ and body fluid homeostasis. Data from animal models of hypertension suggest that the renin-angiotensin system in the subfornical organ (SFO) of the brain is critical for hypertension development. We recently reported that the brain (pro)renin receptor (PRR) is a novel component of the brain renin-angiotensin system and could be a key initiator of the pathogenesis of hypertension. Here, we examined the expression level and cellular distribution of PRR in the SFO of postmortem human brains to assess its association with the pathogenesis of human hypertension. Postmortem SFO tissues were collected from hypertensive and normotensive human subjects. Immunolabeling for the PRR and a retrospective analysis of clinical data were performed. We found that human PRR was prominently expressed in most neurons and microglia, but not in astrocytes, in the SFO. Importantly, PRR levels in the SFO were elevated in hypertensive subjects. Moreover, PRR immunoreactivity was significantly correlated with systolic blood pressure but not body weight, age, or diastolic blood pressure. Interestingly, this correlation was independent of antihypertensive drug therapy. Our data indicate that PRR in the SFO may be a key molecular player in the pathogenesis of human hypertension and, as such, could be an important focus of efforts to understand the neurogenic origin of hypertension. NEW & NOTEWORTHY This study provides evidence that, in the subfornical organ of the human brain, the (pro)renin receptor is expressed in neurons and microglia cells but not in astrocytes. More importantly, (pro)renin receptor immunoreactivity in the subfornical organ is increased in hypertensive humans and is significantly correlated with systolic blood pressure.

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Abstract P061: Selective Deletion of Intracellular Renin in the Brain Causes Hypertension and Elevated Sympathetic Nervous System Activity

Hypertension ◽

10.1161/hyp.66.suppl_1.p061 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Keisuke Shinohara ◽

Benjamin J Weidemann ◽

Matthew D Folchert ◽

Xuebo Liu ◽

Donald A Morgan ◽

...

Keyword(s):

Blood Pressure ◽

Metabolic Rate ◽

Systolic Blood Pressure ◽

Neural Circuit ◽

Resting Metabolic Rate ◽

Renin Angiotensin System ◽

Power Spectral Analysis ◽

Angiotensin System ◽

Renin Angiotensin ◽

The Brain

Renin expression is regulated by two distinct promoter-1st exon combinations that target renin either for secretion (exon 1a for secreted renin) or cytoplasmic retention (exon 1b for intracellular renin, icREN). We developed icREN knockout (KO) mice by selectively deleting exon 1b. icREN KO mice are essentially brain-specific knockouts of icREN because icREN is predominantly expressed in the brain. Notably, systolic blood pressure measured by telemetry was increased in icREN KO mice (130±2 mmHg, n=8 vs 122±2 mmHg in controls, n=7, P<0.01). The low- to high-frequency ratio (LF/HF) derived from power spectral analysis of heart rate variability, a parameter of sympathetic nerve activity (SNA), was increased in icREN KO mice (KO: 1.24±0.21, n=7 vs control: 0.70±0.11, n=7, P<0.05). Body weight (BW) was normal in icREN KO mice compared to controls, but the BW gain and fat accumulation induced by high fat diet (HFD) were attenuated in male icREN KO mice (BW at 16 wks of HFD- KO: 36.8±1.2 g, n=8 vs control: 41.9±1.4 g, n=9; relative fat mass at 14 wks of HFD- KO: 27.7±1.7%, n=8 vs control: 34.4±2.3%, n=9, both P<0.05). The resting metabolic rate measured by respirometry was increased in icREN KO mice (0.156±0.005 kcal/h, n=46, P<0.05) vs controls (0.145±0.003 kcal/h, n=53), whereas food consumption and absorbed calories were not different. We previously reported that the brain renin-angiotensin system facilitates renal SNA (RSNA) response to acute intracerebroventricular (ICV) injection of leptin. Interestingly, the RSNA response to ICV leptin was greater in icREN KO mice (KO: 214±40 % baseline, n=5 vs control: 114±18 % baseline, n=10, P<0.01). AT1a receptor mRNA was upregulated in the paraventricular nucleus of icREN KO mice (P<0.05). Chronic ICV injection of losartan not only abolished the elevated blood pressure in icREN KO mice, but reduced it to below baseline in controls (systolic blood pressure, 111±3 mmHg in KO, n=5; 124±4 mmHg in controls, n=6). These data suggest that icREN deletion increases the activity of brain renin-angiotensin system and elevates blood pressure and metabolic rate through sympathetic activation. We conclude that this novel icREN isoform contributes to cardiovascular and metabolic control possibly as part of an inhibitory neural circuit.

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Losartan prevents the elevation of blood pressure in adipose-PRR deficient female mice while elevated circulating sPRR activates the renin-angiotensin system

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00473.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. H506-H515 ◽

Cited By ~ 6

Author(s):

Eva Gatineau ◽

Dianne M. Cohn ◽

Marko Poglitsch ◽

Analia S. Loria ◽

Ming Gong ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Renin Angiotensin System ◽

Soluble Form ◽

Ang Ii ◽

High Fat ◽

Angiotensin System ◽

Renin Angiotensin ◽

Female Mice ◽

Prorenin Receptor

Deletion of the prorenin receptor (PRR) in adipose tissue elevates systolic blood pressure (SBP) and the circulating soluble form of PRR (sPRR) in male mice fed a high-fat (HF) diet. However, sex differences in the contribution of adipose-PRR and sPRR to the regulation of the renin-angiotensin system (RAS) in key organs for blood pressure control are undefined. Therefore, we assessed blood pressure and the systemic and intrarenal RAS status in adipose-PRR knockout (KO) female mice. Blockade of RAS with losartan blunted SBP elevation in HF diet-fed adipose-PRR KO mice. ANG II levels were significantly increased in the renal cortex of HF diet-fed adipose-PRR KO female mice, but not systemically. HF diet-fed adipose-PRR KO mice exhibited higher vasopressin levels, water retention, and lower urine output than wild-type (WT) mice. The results also showed that deletion of adipose-PRR increased circulating sPRR and total hepatic sPRR contents, suggesting the liver as a major source of elevated plasma sPRR in adipose-PRR KO mice. To mimic the elevation of circulating sPRR and define the direct contribution of systemic sPRR to the regulation of the RAS and vasopressin, C57BL/6 female mice fed a standard diet were infused with recombinant sPRR. sPRR infusion increased plasma renin levels, renal and hepatic angiotensinogen expression, and vasopressin. Together, these results demonstrate that the deletion of adipose-PRR induced an elevation of SBP likely mediated by an intrarenal ANG II-dependent mechanism and that sPRR participates in RAS regulation and body fluid homeostasis via its capacity to activate the RAS and increase vasopressin levels. NEW & NOTEWORTHY The elevation of systolic blood pressure appears to be primarily mediated by cortical ANG II in high-fat diet-fed adipose-prorenin receptor knockout female mice. In addition, our data support a role for soluble prorenin receptor in renin-angiotensin system activation and vasopressin regulation.

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Renin-angiotensin System (RAS)-mediated Antiobesity and Antihypertensive Effects of Korean Traditional Soybean Paste (Doenjang) in Rat Model of Diet-induced Obesity (P08-097-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p08-097-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Hayoung Woo ◽

Jung Eun Park ◽

Youn-soo Cha

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

High Fat Diet ◽

Health Benefits ◽

Renin Angiotensin System ◽

Serum Chemistry ◽

Table Salt ◽

High Fat ◽

Angiotensin System ◽

Renin Angiotensin

Abstract Objectives Hypertension is becoming more prevalent and one of the main cause is found in the increase of excessive dietary sodium intake. It is also risk factors for cardiovascular and kidney disease. Korean Traditional Fermented Food, doenjang, is made with high salt, so many of them are thinking that there is a lot of relation to hypertension despite reporting many health benefits. Our previous studies reported that doenjang have been associated effect of anti-obesity in human and animal study. Therefore, we expected that doenjang may have different effects on blood pressure and lipid metabolism compared to same concentrations of salt. Methods In this study, Sprague-Dawley rats divided into four groups, normal diet (ND), high fat diet (HD), high fat diet with 8% table salt (HDS), high fat diet with Doenjang contains 8% table salt (HDJ) for 13 weeks. The systolic blood pressure (SBP), serum chemistry, Na+ and K+ concentrations, liver and renal gene expressions were measured. Results Doenjang decreased systolic blood pressure (SBP), body weight and hepatic lipids. Serum chemistry, leptin and aldosterone levels were increased in HD and HDS groups while decreased in HDJ group. Results from analysing feces and urine, Na+, Ca+ and K+concentrations were changed by Doenjang. Furthermore, fatty acid synthesis-related genes expression was decreased in liver and downregulated the renin, AT1 receptor and ACE in renal cortex of doenjang treatment group. Conclusions These results suggest that doenjang may have anti-obesity and anti-hypertension through regulation of the renin angiotensin system. We believed that it is an important result of demonstrating that doenjang has health benefits regardless of salt content. Funding Sources This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2018R1A2B6006477).

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B022 Acute blood pressure response to captopril analised by the area under the curve method correlates with renin angiotensin system

American Journal of Hypertension ◽

10.1016/s0895-7061(97)90865-7 ◽

1998 ◽

Vol 11 (4) ◽

pp. 45A

Author(s):

L MATAVELLI

Keyword(s):

Blood Pressure ◽

Blood Pressure Response ◽

Area Under The Curve ◽

Renin Angiotensin System ◽

Pressure Response ◽

Angiotensin System ◽

Renin Angiotensin ◽

Curve Method

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The Role of the Renin-Angiotensin System in the Control of Blood Pressure and Drinking in the European Eel, Anguilla anguilla

General and Comparative Endocrinology ◽

10.1006/gcen.1995.1130 ◽

1995 ◽

Vol 100 (1) ◽

pp. 39-48 ◽

Cited By ~ 47

Author(s):

M.L. Tierney ◽

G. Luke ◽

G. Cramb ◽

N. Hazon

Keyword(s):

Blood Pressure ◽

Renin Angiotensin System ◽

Anguilla Anguilla ◽

European Eel ◽

Angiotensin System ◽

Renin Angiotensin

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Terlipressin Versus Norepinephrine to Correct Refractory Arterial Hypotension after General Anesthesia in Patients Chronically Treated with Renin-Angiotensin System Inhibitors

Anesthesiology ◽

10.1097/00000542-200306000-00007 ◽

2003 ◽

Vol 98 (6) ◽

pp. 1338-1344 ◽

Cited By ~ 55

Author(s):

Gilles Boccara ◽

Alexandre Ouattara ◽

Gilles Godet ◽

Eric Dufresne ◽

Michèle Bertrand ◽

...

Keyword(s):

Blood Pressure ◽

General Anesthesia ◽

Arterial Blood Pressure ◽

Renin Angiotensin System ◽

Arterial Hypotension ◽

Angiotensin System ◽

Renin Angiotensin ◽

Arterial Blood ◽

Long Term Treatment ◽

Systolic Arterial Blood Pressure

Background Terlipressin, a precursor that is metabolized to lysine-vasopressin, has been proposed as a drug for treatment of intraoperative arterial hypotension refractory to ephedrine in patients who have received long-term treatment with renin-angiotensin system inhibitors. The authors compared the effectiveness of terlipressin and norepinephrine to correct hypotension in these patients. Methods Among 42 patients scheduled for elective carotid endarterectomy, 20 had arterial hypotension following general anesthesia that was refractory to ephedrine. These patients were the basis of the study. After randomization, they received either 1 mg intravenous terlipressin (n = 10) or norepinephrine infusion (n = 10). Beat-by-beat recordings of systolic arterial blood pressure and heart rate were stored on a computer. The intraoperative maximum and minimum values of blood pressure and heart rate, and the time spent with systolic arterial blood pressure below 90 mmHg and above 160 mmHg, were used as indices of hemodynamic stability. Data are expressed as median (95% confidence interval). Results Terlipressin and norepinephrine corrected arterial hypotension in all cases. However, time spent with systolic arterial blood pressure below 90 mmHg was less in the terlipressin group (0 s [0-120 s] vs. 510 s [120-1011 s]; P < 0.001). Nonresponse to treatment (defined as three boluses of terlipressin or three changes in norepinephrine infusion) occurred in zero and eight cases (P < 0.05), respectively. Conclusions In patients who received long-term treatment with renin-angiotensin system inhibitors, intraoperative refractory arterial hypotension was corrected with both terlipressin and norepinephrine. However, terlipressin was more rapidly effective for maintaining normal systolic arterial blood pressure during general anesthesia.

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Divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00575.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. R313-R320 ◽

Cited By ~ 15

Author(s):

Curt D. Sigmund

Keyword(s):

Blood Pressure ◽

Fluid Intake ◽

Renin Angiotensin System ◽

Metabolic Effects ◽

Angiotensin System ◽

Renin Angiotensin ◽

Intracellular Form ◽

Efferent Pathways ◽

The Brain ◽

Pituitary Adrenal Axis

The purpose of this review is two-fold. First, I will highlight recent advances in our understanding of the mechanisms regulating angiotensin II (ANG II) synthesis in the brain, focusing on evidence that renin is expressed in the brain and is expressed in two forms: a secreted form, which may catalyze extracellular ANG I generation from glial or neuronal angiotensinogen (AGT), and an intracellular form, which may generate intracellular ANG in neurons that may act as a neurotransmitter. Second, I will discuss recent studies that advance the concept that the renin-angiotensin system (RAS) in the brain not only is a potent regulator of blood pressure and fluid intake but may also regulate metabolism. The efferent pathways regulating the blood pressure/dipsogenic effects and the metabolic effects of elevated central RAS activity appear different, with the former being dependent upon the hypothalamic-pituitary-adrenal axis, and the latter being dependent upon an interaction between the brain and the systemic (or adipose) RAS.

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