scholarly journals Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

2011 ◽  
Vol 300 (4) ◽  
pp. H1484-H1491 ◽  
Author(s):  
Javad Habibi ◽  
Vincent G. DeMarco ◽  
Lixin Ma ◽  
Lakshmi Pulakat ◽  
William E. Rainey ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Diastolic Dysfunction ◽  
Mineralocorticoid Receptor ◽  
Low Dose ◽  
Left Ventricular ◽  
Receptor Blockade ◽  
Conventional Dose ◽  
Mineralocorticoid Receptor Blockade

There is emerging evidence that aldosterone can promote diastolic dysfunction and cardiac fibrosis independent of blood pressure effects, perhaps through increased oxidative stress and inflammation. Accordingly, this investigation was designed to ascertain if mineralocorticoid receptor blockade improves diastolic dysfunction independently of changes in blood pressure through actions on myocardial oxidative stress and fibrosis. We used young transgenic (mRen2)27 [TG(mRen2)27] rats with increases in both tissue ANG II and circulating aldosterone, which manifests age-related increases in hypertension and cardiac dysfunction. Male TG(mRen2)27 and age-matched Sprague-Dawley rats were treated with either a low dose (∼1 mg·kg−1·day−1) or a vasodilatory, conventional dose (∼30 mg·kg−1·day−1) of spironolactone or placebo for 3 wk. TG(mRen2)27 rats displayed increases in systolic blood pressure and plasma aldosterone levels as well as impairments in left ventricular diastolic relaxation without changes in systolic function on cine MRI. TG(mRen2)27 hearts also displayed hypertrophy (left ventricular weight, cardiomyoctye hypertrophy, and septal wall thickness) as well as fibrosis (interstitial and perivascular). There were increases in oxidative stress in TG(mRen2)27 hearts, as evidenced by increases in NADPH oxidase activity and subunits as well as ROS formation. Low-dose spironolactone had no effect on systolic blood pressure but improved diastolic dysfunction comparable to a conventional dose. Both doses of spironolactone caused comparable reductions in ROS/3-nitrotryosine immunostaining and perivascular and interstitial fibrosis. These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure.

Mineralocorticoid Receptor Blockade Reduced Oxidative Stress in Renal Transplant Recipients: A Double-Blind, Randomized Pilot Study

2013 ◽  
Vol 37 (5) ◽  
pp. 481-490 ◽  
Author(s):  
Marcos Ojeda-Cervantes ◽  
Jonatan Barrera-Chimal ◽  
Josefina Alberú ◽  
Rosalba Pérez-Villalva ◽  
Luis Eduardo Morales-Buenrostro ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pilot Study ◽  
Renal Transplant ◽  
Mineralocorticoid Receptor ◽  
Renal Transplant Recipients ◽  
Receptor Blockade ◽  
Transplant Recipients ◽  
Double Blind ◽  
Mineralocorticoid Receptor Blockade

Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA–salt hypertension

2002 ◽  
Vol 436 (3) ◽  
pp. 207-216 ◽  
Author(s):  
Kamal Rahmouni ◽  
Rosana M. Sibug ◽  
E.Ronald De Kloet ◽  
Mariette Barthelmebs ◽  
Michèle Grima ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mineralocorticoid Receptor ◽  
Receptor Blockade ◽  
Renal Functions ◽  
Salt Hypertension ◽  
Mineralocorticoid Receptor Blockade

Abstract 14069: Subclinical Impairment of Left Ventricular Function in Stage A Subjects in a Community-based Population

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Takuya Hasegawa ◽  
Masanori Asakura ◽  
Hideaki Kanzaki ◽  
Hiroshi Asanuma ◽  
Seiji Takashio ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Diastolic Dysfunction ◽  
Left Ventricular ◽  
Community Dwelling ◽  
Lv Function ◽  
Mitral Annular Velocity ◽  
Lv Mass ◽  
Lv Diastolic Dysfunction

Introduction: Stage A heart failure (HF) is defined as an asymptomatic state with HF risk factors of hypertension, diabetes, obesity, metabolic syndrome, and atherosclerotic disease in the absence of obvious left ventricular (LV) structural changes including LV hypertrophy (LVH). ACC/AHA guidelines recommend us to treat these risk factors of Stage A HF patients to prevent the progression of HF, hinting us to investigate the prevalence of subclinical impairment of LV function in Stage A subjects in general populations. Methods: We studied 1162 community-dwelling subjects without obvious heart diseases (mean age, 63±11 years; 448 men, 714 women, 63% with hypertension and 11% with diabetes) in the annual health checkup in a rural community, Arita-cho, Saga, Japan. The population was divided into 3 groups; the subjects without either LVH or the HF risk factors ("Stage 0"), the subjects with the HF risk factors in the absence of LVH (Stage A) , and the subjects in the presence of LVH (Stage B). LV systolic and diastolic function were estimated by mitral annular velocity in systole (s'), and the waves of transmitral flow (E) and mitral annular velocity (e'), respectively. LVH was defined as the top quintile of LV mass index. Results: The subjects in Stage A had the lower and higher values of s' and E/e', respectively, and the higher prevalence of LV diastolic dysfunction than those in Stage 0, while 45% of Stages A subjects showed LV diastolic dysfunction (Table). In multivariate logistic analyses, age, systolic blood pressure and LV mass were independent determinants of s', whereas either overlapped or different risk factors, such as age, sex, systolic blood pressure, and body mass index emerged as the determinants for E/e'. Conclusions: Even without obvious LV remodeling, subclinical LV systolic and diastolic impairment was observed in Stage A subjects. The disparity of the risk factors between LV systolic and diastolic dysfunction may indicate their pathophysiological differences.

scholarly journals Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3416-3425 ◽  
Author(s):  
Laura A. Bienvenu ◽  
James Morgan ◽  
Amanda J. Rickard ◽  
Greg H. Tesch ◽  
Greg A. Cranston ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Mineralocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Plasma Aldosterone ◽  
Mrna Levels ◽  
Wild Type ◽  
And Oxidative Stress

Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type l-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both l-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by l-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both l-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type l-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, l-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.

scholarly journals Low-Dose Curcumin Nanoparticles Normalise Blood Pressure in Male Wistar Rats with Diet-Induced Metabolic Syndrome

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1542 ◽  
Author(s):  
Ryan du Preez ◽  
Jessica Pahl ◽  
Meenakshi Arora ◽  
M. N. V. Ravi Kumar ◽  
Lindsay Brown ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Systolic Blood Pressure ◽  
Wistar Rats ◽  
Low Dose ◽  
Left Ventricular ◽  
High Dose ◽  
Curcumin Nanoparticles ◽  
Diastolic Stiffness ◽  
Male Wistar Rats

Nanoparticle formulations improve bioavailability and so may allow low-dose formulations of food-derived compounds such as curcumin to attenuate chronic systemic disease despite intrinsically low oral bioavailability. The current study induced metabolic syndrome in male Wistar rats aged eight–nine weeks using a high-carbohydrate, high-fat diet (H) with corn starch diet (C) as control. Using a reversal protocol, rats were given curcumin as either nanoparticles encapsulated in poly(lactic–co–glycolic acid) (5 mg/kg/day, HCNP) or as an unformulated low dose or high-dose suspension in water (low-dose, 5 mg/kg/day, HC5; high-dose, 100 mg/kg/day, HC100) or blank nanoparticles (HBNP) for the final eight weeks of the 16 week study. We analysed cardiovascular parameters including systolic blood pressure and left ventricular diastolic stiffness along with histopathology, liver parameters including plasma liver enzymes, histopathology and metabolic parameters, including glucose tolerance, blood lipid profile and body composition, and plasma curcumin concentrations. HC100 and HCNP but not HBNP normalised systolic blood pressure (C = 120 ± 4; H = 143 ± 5; HBNP = 141 ± 3; HC5 = 143 ± 4; HC100 = 126 ± 4; HCNP = 128 ± 4 mmHg), left ventricular diastolic stiffness and liver fat deposition. No other improvements were induced in HC100 or HCNP or other intervention groups (HC5 and HBNP). We conclude that 5 mg/kg/day curcumin nanoparticles in H rats showed similar improvements in cardiovascular function as 100 mg/kg/day unformulated curcumin correlating with similar plasma curcumin concentrations.

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