Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction

1999 ◽  
Vol 276 (5) ◽  
pp. H1608-H1615 ◽  
Author(s):  
Weiguo Zhang ◽  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Renin Angiotensin System ◽  
Coronary Artery Ligation ◽  
Arterial Baroreflex ◽  
Baroreflex Control ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Air Jet ◽  
Baroreflex Function ◽  
The Brain

Blockade of brain “ouabain” prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain “ouabain” may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg ⋅ kg−1 ⋅ day−1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the α2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.

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.

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

2005 ◽  
Vol 288 (5) ◽  
pp. H2491-H2497 ◽  
Author(s):  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mineralocorticoid Receptors ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function ◽  
Adrenoceptor Agonist ◽  
The Brain

In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng·kg−1·h−1) or its vehicle, or with benzamil (4 μg·kg−1·h−1) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the α2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (∼31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.

ANG II receptor blockade and arterial baroreflex regulation of renal nerve activity in cardiac failure

1995 ◽  
Vol 269 (5) ◽  
pp. R1189-R1196 ◽  
Author(s):  
G. F. DiBona ◽  
S. Y. Jones ◽  
V. L. Brooks
Keyword(s):  
Arterial Pressure ◽  
Cardiac Failure ◽  
Renin Angiotensin System ◽  
Receptor Blockade ◽  
Arterial Baroreflex ◽  
Nerve Activity ◽  
Renal Nerve ◽  
Baroreflex Control ◽  
Angiotensin System ◽  
Renin Angiotensin

In cardiac failure, efferent renal sympathetic nerve activity (ERSNA) and the activity of the renin-angiotensin system are increased, and arterial baroreflex regulation of ERSNA is attenuated. We examined the effect of intravenous and intracerebroventricular angiotensin II AT receptor blockade with losartan on the arterial baroreflex regulation of ERSNA in conscious control (C) and congestive heart failure (CHF) rats. Intravenous losartan (10 mg/kg, 21.7 mumol/kg) decreased arterial pressure more in CHF than in C rats (-28 +/- 3 vs. -20 +/- 3 mmHg, P < 0.05). After restoration of arterial pressure to the prelosartan value with methoxamine infusion, ERSNA was decreased more in CHF than in C rats (-23 +/- 4 vs. -1 +/- 2%, P < 0.05). Maximal gain of arterial baroreflex control of ERSNA (Gmax) was lower in CHF compared with C rats (-1.94 +/- 0.10 vs. -3.78 +/- 0.21%/mmHg, P < 0.05). Intravenous losartan increased Gmax in CHF (to -3.01 +/- 0.14%/mmHg, P < 0.05) but not in C rats (to -3.56 +/- 0.19%/mmHg). Intracerebroventricular losartan (4.61 micrograms, 10 nmol) did not affect arterial pressure but decreased ERSNA more in CHF than in C rats (-13 +/- 2 vs. -8 +/- 3%, P < 0.05). Like intravenous losartan, intracerebroventricular losartan increased Gmax in CHF (from -2.11 +/- 0.18 to -3.21 +/- 0.30%/mmHg, P < 0.05) but not in C rats (from -3.98 +/- 0.25 to -3.84 +/- 0.22%/mmHg). These results suggest that increased activity of the renin-angiotensin system contributes to the increase in ERSNA and its abnormal arterial baroreflex regulation in cardiac failure.

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

2012 ◽  
Vol 302 (3) ◽  
pp. R313-R320 ◽  
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.

The Brain-Renin-Angiotensin System: Update

1986 ◽  
pp. 123-133 ◽  
Author(s):  
Thomas Unger ◽  
Detlev Ganten ◽  
Gerald Ludwig ◽  
Rudolf E. Lang
Keyword(s):  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
The Brain

The renin angiotensin system and the brain: New developments

2017 ◽  
Vol 46 ◽  
pp. 1-8 ◽  
Author(s):  
Ehab Farag ◽  
Daniel I. Sessler ◽  
Zeyd Ebrahim ◽  
Andrea Kurz ◽  
Joseph Morgan ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Angiotensin System ◽  
New Developments ◽  
Renin Angiotensin ◽  
The Brain

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.

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