Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure

Cell Calcium ◽  
2020 ◽  
Vol 86 ◽  
pp. 102151 ◽  
Author(s):  
Frans H.H. Leenen ◽  
Hong-Wei Wang ◽  
John M. Hamlyn
Keyword(s):  
Heart Failure ◽  
Sodium Pumps ◽  
Salt Sensitive Hypertension ◽  
The Brain

The brain in congestive heart failure

1996 ◽  
Vol 23 (3) ◽  
pp. 247-256 ◽  
Author(s):  
D. Acanfora ◽  
L. Trojano ◽  
G.L. Iannuzzi ◽  
G. Furgi ◽  
C. Picone ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
The Brain

Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Joseph Francis ◽  
Li Yu ◽  
Anuradha Guggilam ◽  
Srinivas Sriramula ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Neuronal Nos ◽  
The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

Chronic heart failure: a disease of the brain

2018 ◽  
Vol 24 (2) ◽  
pp. 301-307 ◽  
Author(s):  
Ram B. Singh ◽  
Krasimira Hristova ◽  
Jan Fedacko ◽  
Galal El-Kilany ◽  
Germaine Cornelissen
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
The Brain

Abstract MP57: Chronic Inhibition Of Brain Rhomboid-like Protein 2 (irhom2) Activity Decreases Arterial Blood Pressure In Salt-sensitive Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Mazher Mohammed ◽  
Mona Elgazzaz ◽  
Clara Berdasco ◽  
Eric D Lazartigues
Keyword(s):  
Blood Pressure ◽  
Neutralizing Antibody ◽  
Experimental Models ◽  
Arterial Blood ◽  
Artificial Cerebrospinal Fluid ◽  
Tnf Α ◽  
Significant Attenuation ◽  
Factor Α ◽  
Salt Sensitive Hypertension ◽  
The Brain

We previously reported that ADAM17 (aka tumor necrosis factor-α convertase) is critical for the development of hypertension in experimental models and patients. Recent studies highlighted that ADAM17’s formation of TNF-α relies on prior maturation of this sheddase, controlled by the rhomboid-like protein 2 (iRhom2) specifically in microglia. Genetic deletion of iRhom2 in mice shows significant attenuation of TNF-α and ADAM17 activity in a tissue specific manner. Here, we hypothesized that silencing iRhom2 activity specifically in the brain would decrease blood pressure (BP) in the DOCA-salt model of hypertension, in mice. Uninephrectomized mice were implanted subcutaneously (sc) with DOCA-pellets (50 mg) and provided with 1% saline in drinking water. In addition, mice were chronically implanted with an icv cannula connected to a sc osmotic minipump for delivery of: (1) iRhom2-siRNA (9.6 μg/kg/day), (2) scrambled siRNA (SCR 0.2 μg/kg/day), (3) ADAM17 antibody (ADAM17-Ab; 23.8 μg/kg/day) or (4) artificial cerebrospinal fluid (aCSF) for 2 weeks while BP was recorded by telemetry. DOCA-salt treatment led to a significant increase in BP in the control groups (SCR: 156 ±3 mmHg and aCSF: 161 ±1 mmHg; n=3/group; p<0.001) compared to baseline values (122 ±2 mmHg; n=12). ICV infusion of iRhom2-siRNA or ADAM17 neutralizing antibody for 2-weeks in DOCA-salt-treated mice resulted in a significant attenuation of BP (iRhom2-siRNA: 152 ±2 mmHg and ADAM17-Ab: 151 ±2 mmHg n=3/group, p<0.001). These data suggest that: 1) Selective silencing of iRhom2 from microglia is as potent as ADAM17 neutralization throughout the brain in lowering BP and 2) iRhom2 is a potential new therapeutic target for the treatment of salt-sensitive hypertension.

Abstract 1375: Brain Renin Angiotensin Blockade Attenuates Cytokines and Oxidative Stress in the Paraventricular Nucleus of Hypothalamus and Decreases Sympathoexcitation in Heart Failure Rats

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ying Ma ◽  
Yu-Ming Kang* ◽  
Zhi-Ming Yang ◽  
Joseph Francis*
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Paraventricular Nucleus ◽  
Cross Talk ◽  
Renin Angiotensin System ◽  
Heart Weight ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain ◽  
And Oxidative Stress

Introduction: Neurohumoral mechanisms play an important role in the pathophysiology of congestive heart failure (HF). Recent studies suggest that the brain renin angiotensin system (RAS) plays an important role in regulating body fluids and sympathetic drive in HF. In addition, it has been shown that there is cross talk between cytokines and RAS in cardiovascular disease. In this study we determined whether blockade of brain RAS attenuate inflammatory cytokines and oxidative stress in HF rats. Methods and Results: Adult male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannulae and subjected to coronary artery ligation to induce HF and confirmed by echocardiography. Rats were treated with an angiotensin type 1 receptors (AT1-R) antagonist losartan (LOS, 20 μg/hr, ICV) or vehicle (VEH) for 4 weeks. At the end of the study, left ventricular (LV) function was measured by echocardiography and rats were sacrificed, and brain and plasma samples were collected for measurements of cytokines and superoxide using immunohistochemistry, Western blot and real time RT-PCR. HF rats induced significant increases in Nuclear Factor-kappaB (NF-κB) p50-positive neurons and activated microglia in the paraventricular nucleus (PVN) of hypothalamus, and TNF-α, IL-1β, IL-6 and NF-κB p50 in hypothalamus when compared with sham rats. These animals also had increased staining for dihydroethidium (DHE) and plasma levels of norepinephrine (NE), an indirect indicator of sympathetic activity. In contrast, ICV treatment with LOS attenuated cytokine expression and oxidative stress in the PVN and hypothalamus when compared with VEH treated HF rats. ICV treatment with LOS also reduced plasma NE levels, and proinflammatory cytokine, heart weight to body weight ratio with decreased LV end-diastolic pressure. Conclusions : These findings suggest the cross talk between the cytokines and renin angiotensin system within the brain contribute to sympatho-excitation in HF.

Abstract MP06: Kinin B1 Receptor Mediates Orexin System Hyperactivity In Salt-sensitive Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Rohan U Parekh ◽  
Abdel A Abdel-rahman ◽  
Srinivas Sriramula
Keyword(s):  
Radio Telemetry ◽  
Mrna Levels ◽  
Wild Type ◽  
Salt Treatment ◽  
Neurogenic Hypertension ◽  
B1 Receptor ◽  
Kinin B1 Receptor ◽  
Salt Sensitive Hypertension ◽  
The Brain

Hyperactivity of the orexin system contributes to several animal models of hypertension and enhances arginine vasopressin (AVP) release. We previously reported higher neuronal kinin B1 receptor (B1R) expression and brain AVP levels in hypertensive mice. However, the role of B1R and its interaction with orexin system in neurogenic hypertension have not been studied. In the present study, we tested the hypothesis that kinin B1R contributes to hypertension by upregulation of orexin-AVP signaling in the brain. Deoxycorticosterone acetate (DOCA)-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of wild-type (WT) male mice produced a significant increase in mean arterial pressure (MAP; radio-telemetry) (138 ±3 mmHg, n=8, p<0.01) that was blunted in B1R knockout mice (121±2 mmHg, P <0.05 vs. WT+DOCA). In WT mice, DOCA-salt, compared to vehicle, increased mRNA levels of orexin receptor 1 (2.5 fold, n=9, p<0.001), orexin receptor 2 (3 fold, n=9, p<0.001) and AVP (3 fold, n=9, p<0.01) in the hypothalamic paraventricular nucleus (PVN), and these DOCA-salt evoked effects were attenuated in B1RKO mice. Similarly, DOCA-salt evoked increases in protein expression of orexin receptor 1 and 2 in the hypothalamic PVN of WT mice were attenuated by 25±5% and 33±5% (p<0.05), respectively, in B1RKO vs WT+DOCA mice. Furthermore, DOCA-salt treatment increased plasma AVP levels in WT mice compared to vehicle treated mice (13.69±1.1 vs. 47.86±8.7 pg/ml, p<0.05), but not in B1RKO mice. Together, these data provide novel evidence that kinin B1R plays an important role in mediating DOCA-salt induced hypertension possibly via upregulating the orexin-AVP signaling in the brain.

Brain “ouabain” and angiotensin II contribute to cardiac dysfunction after myocardial infarction

1999 ◽  
Vol 277 (5) ◽  
pp. H1786-H1792 ◽  
Author(s):  
Frans H. H. Leenen ◽  
Baoxue Yuan ◽  
Bing S. Huang
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Renin Angiotensin System ◽  
Volume Overload ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Fab Fragments ◽  
The Brain

In chronic heart failure (CHF), sympathetic activity increases in parallel with the impairment of left ventricle (LV) function, and sympathetic hyperactivity has been postulated to contribute to the progression of heart failure. In the brain, compounds with ouabain-like activity (“ouabain,” for brevity) and the renin-angiotensin system contribute to sympathetic hyperactivity in rats with CHF after myocardial infarction (MI). In the present studies, we assessed whether, in rats, chronic blockade of brain “ouabain” or the brain renin-angiotensin system inhibits the post-MI LV dysfunction. In rats, an MI was induced by acute coronary artery ligation. At either 0.5 or 4 wk post-MI, chronic treatment with Fab fragments for blocking brain “ouabain” or with losartan for blocking brain AT1 receptors was started and continued until 8 wk post-MI using osmotic minipumps connected to intracerebroventricular cannulas. At 8 wk post-MI, in conscious rats, LV pressures were measured at rest and in response to volume and pressure overload, followed by LV passive pressure-volume curves in vitro. At 8 wk post-MI, control MI rats exhibited clear increases in LV end-diastolic pressure (LVEDP) at rest and in response to pressure and volume overload. LV pressure-volume curves in vitro showed a marked shift to the right. Intravenous administration of the Fab fragments or losartan at rates used for central blockade did not affect these parameters. In contrast, chronic central blockade with either Fab fragments or losartan significantly lowered LVEDP at rest (only in 0.5- to 8-wk groups) and particularly in response to pressure or volume overload. LV dilation, as assessed from LV pressure-volume curves, was also significantly inhibited. These results indicate that chronic blockade of brain “ouabain” or brain AT1 receptors substantially inhibits development of LV dilation and dysfunction in rats post-MI.

scholarly journals Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure

2008 ◽  
Vol 295 (1) ◽  
pp. H227-H236 ◽  
Author(s):  
Yu-Ming Kang ◽  
Zhi-Hua Zhang ◽  
Baojian Xue ◽  
Robert M. Weiss ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Hpa Axis ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Left Ventricular ◽  
Prostaglandin E ◽  
Renin Angiotensin ◽  
Intracerebroventricular Infusion ◽  
Cytokine Synthesis ◽  
The Brain

The expression of proinflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic proinflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 wk with a continuous intracerebroventricular infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 μg/h) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of proinflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin-converting enzyme, angiotensin type 1 receptor) and corticotropin-releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of the hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E2) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, ANG II, interleukin (IL)-1β, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1β, an indicator of peripheral proinflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebroventricular PTX. These findings suggest that the increase in brain proinflammatory cytokines observed in rats with ischemia-induced HF is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.

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