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. Author manuscript; available in PMC: 2009 Dec 8.
Published in final edited form as: Hypertension. 2008 Jan 28;51(3):727–733. doi: 10.1161/HYPERTENSIONAHA.107.099796

Does Aldosterone Upregulate the Brain Renin-Angiotensin System in Rats with Heart Failure?

Yang Yu 1, Shun-Guang Wei 1, Zhi-Hua Zhang 1, Elise Gomez-Sanchez 3, Robert M Weiss 1,2, Robert B Felder 1,2
PMCID: PMC2790402  NIHMSID: NIHMS149518  PMID: 18227408

Abstract

The brain renin-angiotensin system (RAS) contributes to increased sympathetic drive in heart failure (HF). The factors upregulating the brain RAS in HF remain unknown. We hypothesized that aldosterone (ALDO), a downstream product of the systemic RAS that crosses the blood-brain barrier, signals the brain to increase RAS activity in HF. We examined the relationship between circulating and brain ALDO in normal intact rats, in adrenalectomized rats receiving subcutaneous infusions of ALDO, and in rats with ischemia-induced HF and sham-operated controls (SHAM). Brain ALDO levels were proportional to plasma ALDO levels across the spectrum of rats studied. Compared with SHAM rats, HF rats had higher plasma and hypothalamic tissue levels of ALDO. HF rats also had higher expression of mRNA and protein for angiotensin converting enzyme (ACE) and angiotensin type 1 receptors (AT1-R) in hypothalamus, increased reduced nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase activity and superoxide generation in paraventricular nucleus (PVN) of hypothalamus, increased excitation of PVN neurons, and increased plasma norepinephrine (NE). HF rats treated for 4 weeks with intracerebroventricular RU28318 (1 μg/hr), a selective mineralocorticoid receptor antagonist, had less hypothalamic ACE and AT1-R mRNA and protein, less NAD(P)H-induced superoxide in PVN, fewer excited PVN neurons, and lower plasma NE. RU28318 had no effect on plasma ALDO, or on ACE or AT1-R mRNA expression in brain cortex. The data demonstrate that ALDO of adrenal origin enters the hypothalamus in direct proportion to plasma levels, and suggest that ALDO contributes to the upregulation of hypothalamic RAS activity and sympathetic drive in heart failure.

Keywords: hypothalamus, sympathetic nerve activity, superoxide, angiotensin converting enzyme, angiotensin type 1 receptor

INTRODUCTION

The intrinsic brain renin-angiotensin system (RAS) is activated in heart failure. Both angiotensin converting enzyme (ACE), the final step in production of angiotensin II (ANG II), and the angiotensin type 1 receptors (AT1-R) that mediate the central effects of ANG II, are upregulated in cardiovascular regulatory centers of the brain.1, 2 It is generally agreed that ANG II generated by the brain RAS contributes importantly to the augmented sympathetic nervous system activity typical of the heart failure syndrome.3, 4 ANG II in the brain may activate the sympathetic nervous system by stimulating reduced nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase dependent superoxide production 4, 5 or by increasing ion channel activity.6 Selective inhibition of brain ACE activity 7 or of brain AT1-R 8 has been shown to substantially reduce sympathetic activity in heart failure.

Surprisingly little is known about the factors that increase brain RAS activity in heart failure. In the present study, we explored the possibility that circulating aldosterone (ALDO) is one such factor. ALDO is released from the zona glomerulosa of the adrenal glands in response to ANG II. Unlike ANG II, ALDO penetrates the blood-brain barrier,9–13 and ALDO levels measured in whole brain tissue reliably reflect plasma levels.14 In peripheral tissues, ALDO acts upon mineralocorticoid receptors (MR) to increase the synthesis of key components of the RAS both in vitro15,16,17 and in vivo.18,19 In the present study, we explored the hypothesis that ALDO acts similarly in the brain, upregulating RAS activity in a forebrain region that contributes to sympathetic drive in heart failure.

We posed three questions: 1) Does the ALDO concentration in hypothalamic tissue reflect the ALDO level in plasma? 2) Does ALDO increase in the hypothalamus of rats with heart failure? 3) Does activation of brain MR upregulate the synthesis of key components of the brain RAS in the hypothalamus of rats with heart failure? We also examined the effects of blocking brain MR on NAD(P)H mediated superoxide production and neuronal excitation in the paraventricular nucleus (PVN) of hypothalamus, a critical cardiovascular and autonomic center that regulates sympathetic drive in heart failure.20 The PVN was selected for study because ACE and AT1-R are upregulated in the PVN in rats with heart failure,1 and inhibition of AT1-R in the PVN reduces sympathetic drive in rats with HF.21

METHODS

Animals

Intact and adrenalectomized (ADX) adult male Sprague-Dawley rats weighing 250–300 g were obtained from Harlan Inc. (Indianapolis, IN). ADX rats were provided 0.9% saline to replace sodium losses. All rats were housed in temperature (23±2°C) and light controlled animal quarters and were fed rat chow ad libitum. These studies were performed in accordance with the “Guiding Principles for Research Involving Animals and Human Beings.” 22 The experimental procedures were approved by the University of Iowa, Institutional Animal Care and Use Committee.

Experimental protocols

Study 1: Relationship between plasma and hypothalamic ALDO in ADX rats

Sixteen ADX rats were divided into four treatment groups (n=4 for each group) that received no treatment (ADX); subcutaneous ALDO (ADX+ALDO) in doses of 0.1 μg/hr or 0.5 μg/hr; or corticosterone (CORT) 0.1 mg/ml in drinking water (ADX+CORT). The average daily dose of CORT was 2.5 mg/day, determined by measuring water intake. After two weeks of treatment, animals were euthanized with an overdose of pentobarbital. Plasma and hypothalamus tissue were collected for measurement of ALDO level by ELISA. Results were compared with data obtained from normal control rats (n=4).

Study 2: Relationship between plasma and brain ALDO in heart failure rats

Ten rats that underwent coronary artery ligation to induce heart failure (HF, n=5), or a sham surgical procedure (SHAM, n=5), and echocardiography to confirm left ventricular function. They were euthanized 4 weeks later with an overdose of pentobarbital. Plasma, hypothalamus and cortex were collected for measurement of ALDO level by ELISA.

Study 3: Effects of blocking brain MR on the brain RAS in heart failure rats

Eighty rats underwent coronary artery ligation to induce HF (n=54) or SHAM (n=26), and echocardiography to assess left ventricular function. They were divided into three treatment groups: SHAM rats that received no treatment (SHAM, n=26); HF rats that received intracerebroventricular (ICV) infusion of the selective mineralocorticoid receptor antagonist RU28318 at 1 μg/hr (HF+RU28318, n=26); HF rats that received ICV vehicle (artificial cerebrospinal fluid, HF+VEH, n=28). Cannulas for ICV infusion were implanted 1 week prior to coronary ligation, and osmotic minipumps to infuse RU28318 or VEH were implanted within 24 hours after coronary ligation. RU28318 and VEH were infused for 4 weeks. In some rats, a second echocardiogram was obtained near the end of the treatment protocol. After 4 weeks of treatment, rats were anesthetized with pentobarbital to obtain hemodynamic measurements. Approximately 30 minutes later, while still under anesthesia, they were euthanized with an overdose of pentobarbital to collect blood and brain tissues for molecular or perfused with fixative for immunohistochemical studies.

Specific methods

Please see online supplement at http://hyper.ahajournals.org

Statistical Analysis

All data are expressed as mean ± SEM. The significance of differences in mean values were analyzed by two-way repeated-measure ANOVA followed by post hoc Fischer's least significant difference test. Echocardiographic parameters were analyzed using one-way ANOVA followed by Fischer's least significant difference test.

RESULTS

Aldosterone levels in plasma and brain

Adrenalectomized rats

Two weeks after ADX, plasma ALDO was undetectable in untreated-ADX and ADX+CORT rats. ALDO in hypothalamus was present at very low levels (Figure 1A). Compared with untreated or CORT-treated ADX rats, ADX rats treated with ALDO had substantially higher ALDO levels in both plasma and hypothalamus. The ALDO levels in plasma increased with the increase in the infused ALDO dose, and the hypothalamic ALDO levels increased proportionately. ALDO levels in plasma and hypothalamus in the ADX rats infused subcutaneously with ALDO 0.5 μg/hr simulated the values in plasma and hypothalamus of control normal rats.

Figure 1.

Figure 1

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ALDO levels in plasma and brain, and the relationship between plasma and hypothalamic ALDO levels. A, ALDO levels in plasma and hypothalamus of ADX rats receiving no ALDO (ADX), subcutaneous infusion of ALDO by osmotic mini-pump (ADX+ALDO, 0.1 or 0.5 μg/hr), or corticosterone (ADX+CORT, 0.1 mg/ml in drinking water) for 2 weeks after ADX, compared with ALDO levels in normal (Control) rats. n=4 for each group, *P<0.05 vs ADX group. † P<0.05 vs ADX+ALDO (0.1 μg/hr). B, ALDO levels in plasma, hypothalamus and cortex of SHAM and HF rats, and C, plasma ALDO levels in SHAM, HF+VEH and HF+RU28318 rats. n=5–8 for each group, *P<0.05 vs SHAM. D, relationship between plasma ALDO levels and hypothalamic tissue levels of ALDO in normal (Control) rats, ADX rats receiving CORT or varying levels of ALDO supplementation, HF and SHAM rats. All values are expressed as mean ± SEM.

Heart failure rats

HF rats had significantly higher plasma (Figure 1B and 1C) and hypothalamic tissue (Figure 1B) ALDO levels than SHAM rats. The plasma and hypothalamic ALDO levels in the SHAM rats were similar to those observed in the normal control rats and the ADX rats infused with ALDO at 0.5μg/hr.

Correlational analysis

The relationship between plasma and hypothalamic ALDO was examined across a variety of experimental conditions: normal (Control) rats, ADX rats receiving CORT or varying levels of ALDO supplementation, HF and SHAM rats (Figure 1D). Hypothalamic ALDO correlated closely with plasma ALDO over a wide range of plasma ALDO levels, whether circulating ALDO levels were normal (control and SHAM rats), controlled by chronic ALDO infusion, or increased in response to induction of heart failure.

Effects of mineralocorticoid receptor blockade on the brain renin-angiotensin system

Real time PCR revealed that ACE and AT1-R mRNA expression in the hypothalamus was increased 2.7-fold and 2.5-fold, respectively, in HF+VEH rats compared with SHAM rats (Figure 2A and 2B). Compared with HF+VEH rats, HF+RU28318 rats had significantly lower levels of ACE mRNA and AT1-R mRNA in the hypothalamus (by 40% for both). There were no statistically significant changes of ACE and AT1-R mRNA expression in brain cortex among three groups (Figure 2A and 2B).

Figure 2.

Figure 2

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Quantitative comparison of mRNA expression and protein levels for ACE (A and C) and AT1-R (B and D) in the hypothalamus and cortex of SHAM, HF+VEH, and HF+RU28318 rats. Representative Western blots are aligned with the matching grouped data (C and D). Values were expressed as mean ± SEM (n = 6–8 for each group). *P<0.05 vs. SHAM in same region, †P<0.05 vs. HF+VEH in same region.

Western blotting analysis confirmed that protein levels for ACE and AT1-R paralleled mRNA induction (Figure 2C and 2D). ACE and AT1-R proteins were markedly upregulated in hypothalamus of HF+VEH rats compared with SHAM rats. There was significantly less ACE and AT1-R protein in the hypothalamus of HF+RU28318 rats compared with HF+VEH rats. ACE and AT1-R protein levels in brain cortex did not differ among the three groups. The RU28318 treatment had no effect on circulating ALDO in HF rats (Figure 1C).

Effects of mineralocorticoid receptor blockade on brain superoxide production

Compared with SHAM rats, HF+VEH rats exhibited significant increase in hypothalamic mRNA for p47phox and gp91phox, two subunits of NAD(P)H oxidase. These increases were markedly inhibited by ICV infusion of MR blocker RU28318 (Figure 3A). Superoxide production was enhanced in HF rats, and this was also attenuated by ICV infusion with RU28318 (Figure 3B). The NAD(P)H oxidase inhibitor diphenyleneiodonium (at a final concentration of 100 μM) totally blocked the superoxide anion production in the hypothalamic homogenates from both groups (Figure 3B), identifying NAD(P)H oxidase as the predominant source of superoxide formation. Finally, intracellular superoxide production was detected using dihydroethidium (DHE). DHE fluorescence was abundant throughout the PVN in HF+VEH rats, including both presympathetic and neuroendocrine regions, compared with SHAM rats (Figure 4). ICV infusion of RU28318 in HF rats significantly reduced DHE fluorescence in posterior magnocellular and dorsal parvocellular regions, and normalized DHE fluorescence in ventrolateral parvocellular and medial parvocellular regions of PVN (Figure 4B). There was no difference across treatment groups in DHE staining in hypothalamic regions surrounding PVN (data not shown).

Figure 3.

Figure 3

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mRNA expression of p47phox and gp91phox, two representative subunits of NAD(P)H oxidase (A) and superoxide production (B) in the hypothalamus of SHAM, HF+VEH, and HF+RU28318 rats. DPI, diphenyleneiodonium Values were expressed as mean ± SEM (n = 4–8 for each group). *P<0.05 vs. SHAM, †P<0.05 vs. HF+VEH.

Figure 4.

Figure 4

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In situ detection of superoxide by DHE fluorescence. A, Representative laser confocal images from the PVN sections of each group. Scale bar = 200 μm. B, Quantitative comparison of DHE fluorescence in 4 difference regions of the PVN of hypothalamus. Values are expressed as mean ± SEM (n = 3 for each group). *P<0.05 vs. SHAM, †P<0.05 vs. HF+VEH. pm, posterior magnocellular; vlp, ventrolateral parvocellular; mp, medial parvocellular; dp, dorsal parvocellular.

Effects of mineralocorticoid receptor blockade on sympathetic excitation

Central neuronal excitation

The expression of Fra-LI activity was increased diffusely throughout the PVN in HF+VEH rats 4 weeks after coronary ligation, compared with SHAM rats (Figure 5A and 5B). HF+RU28318 rats had fewer Fra-LI-positive PVN neurons than HF+VEH rats, but more than the SHAM rats.

Figure 5.

Figure 5

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Central neuronal excitation and plasma NE level. A, Representative sections from each group showing Fra-LI immunoreactivity among neurons in the PVN. Dark dots indicate single activated neurons. Scale bar = 200 μm. B, Quantification of Fra-LI positive neurons in the PVN of each group. C, Plasma NE, a marker of sympathetic nerve activity, in each group. Values are expressed as mean ± SEM (n=4–8 for each group). *P<0.05 vs. SHAM, †P<0.05 vs. HF+VEH.

Plasma norepinephrine

Plasma norepinephrine (NE), a marker of sympathetic nerve activity, was higher in HF+VEH rats compared to SHAM rats (Figure 5C). Plasma NE levels were lower in HF+RU28318 than HF+VEH rats, but still higher than SHAM rats.

Characteristics of the heart failure rats

HF rats assigned to treatment with RU28318 or VEH were well matched with regard to echocardiographically defined left ventricular (LV) function. Echocardiography performed within 24 hours of coronary ligation revealed that LV ejection fraction (LVEF) was reduced and LV end-diastolic volume (LVEDV) was increased in the rats subjected to coronary artery ligation (HF rats), compared with the sham-operated rats (SHAM rats). Four weeks after coronary artery ligation, echocardiography showed that HF rats treated with RU28318 or VEH still had significant increases in LVEDV and decreases in LVEF, compared with SHAM rats. Treatment with RU28318 had no effect on LVEDV, LVEF or the ischemic zone as a percent of LV circumference in HF rats. The echocardiographic data are shown in Table S2 (please see online supplement at http://hyper.ahajournals.org).

Systolic blood pressure (SBP), LV peak systolic pressure (LVPSP), and the maximum rate of rise of LV pressure (LV dP/dt) were lower, and LV end-diastolic pressure (LVEDP) was higher, in HF+VEH rats than SHAM rats. The right ventricle (RV)/body weight (BW) and wet lung/BW ratios were substantially higher in HF+VEH rats compared with SHAM rats. HF+RU28318 rats had higher LV dP/dt, lower LVEDP, and lower RV/BW and wet lung/BW ratios than HF+VEH rats, but all of these values were still significantly different from SHAM rats. SBP and LVPSP were not affected. There were no significant differences in diastolic blood pressure or heart rate across the experimental groups. The hemodynamic and anatomical data are shown in Table S3 (please see online supplement at http://hyper.ahajournals.org).

DISCUSSION

Novel findings of this study are: 1) hypothalamic tissue concentrations of ALDO correlate closely with plasma concentrations; 2) ALDO increases in the hypothalamus in rats with ischemia-induced heart failure; 3) inhibition of brain MR reduces hypothalamic expression of ACE and AT1-R, two key components of the brain RAS system, in rats with ischemia induced heart failure; 4) inhibition of brain MR reduces the generation of reactive oxygen species in the PVN, an important hypothalamic nucleus that regulates sympathetic drive,20 in rats with heart failure. Concomitantly, as expected, chronic excitation of neurons in the PVN and plasma NE levels decrease. Taken together, these findings strongly suggest that ALDO of adrenal origin, circulating in parallel to angiotensin II, signals the brain to increase renin-angiotensin system activity and thus sympathetic drive in heart failure.

Particularly striking in this study is the relationship between activation of brain MR and the brain RAS. Upregulation of brain RAS activity, with increased ACE and AT1-R binding in the PVN, has been reported previously in this model of heart failure.1 Here we demonstrate that ACE and AT1-R mRNA and protein are increased in the hypothalamus of HF rats, and that chronic inhibition of brain MR significantly reduces hypothalamic RAS activity in heart failure. Concomitantly, NAD(P)H oxidase dependent production of superoxide, a putative downstream mediator of the angiotensin message,23 is decreased in the PVN, along with excitation of PVN neurons and peripheral NE release. Prior studies in animal models of heart failure have found that central interventions that block MR 24 or AT1-R8 or quench superoxide25 all reduce sympathetic nerve activity, but the interplay among these systems is still poorly understood. The present results suggest that activation of MR occurs early in the sequence of central events, facilitating the activity of the brain RAS and ultimately leading to sympatho-excitation. This interpretation is consistent with previous studies demonstrating that ALDO increases the binding of angiotensin II to its receptors in the PVN,26 and that subcutaneously administered ALDO has a synergistic interaction with centrally administered angiotensin II on sodium consumption, arterial pressure, and other central effects of angiotensin II.27

ALDO is not the only natural ligand for brain MR. Corticosterone (in rat), or cortisol (in human) binds to brain MR with equal affinity.28 However, subsets of MR in peripheral tissues29 and in brain30 are protected from activation by corticosterone, and thus preserved for activation by ALDO, by co-localization with the enzyme 11β-hydroxysteroid dehydrogenase type 2. The genomic influences of ALDO-sensitive MR are inhibited by classical MR antagonists like RU28318.

The present study demonstrates that tissue levels of ALDO are high in the hypothalamus of HF rats, mirroring the high levels in plasma. In peripheral tissues, such increases in ALDO lead to upregulation of tissue RAS activity. For example, in rats infused with ALDO, ACE mRNA and protein and ACE activity increase in aortic tissue, along with tissue content of ANG II and NAD(P)H oxidase subunits,18 and all these effects that are prevented with an MR antagonist. In rats with ischemia-induced heart failure, an MR antagonist prevents increases in ACE, NAD(P)H oxidase subunit p22phox, and reactive oxygen species in aortic tissue.19 In the present study, an MR antagonist prevents the increases in ACE and NAD(P)H oxidase activity and superoxide in the hypothalamus – similar results, suggesting that the actions of ALDO in the brain closely resemble those in the periphery.

The extent to which these influences of ALDO on local tissue RAS indicate ALDO-induced gene transcription, versus downstream responses to more limited genomic effects of ALDO, cannot be fully addressed in these in vivo studies. In vitro studies suggest that ALDO induces gene expression of ACE 15,16 and renin,17 and so may simply facilitate the synthesis of ANG II. In vivo, an ALDO-induced increase in ANG II might then account for the observed increases in NAD(P)H oxidase activity and upregulation of AT1-R. Thus, while ALDO may activate NAD(P)H oxidase independently,31 it may also increase NAD(P)H oxidase activity by increasing the ANG II available for binding to AT1-R. Similarly, ALDO may increase the expression of AT1-R by upregulating components of the mitogen-activated protein kinase/activator protein-1 signaling pathway,32 or simply by generating more ANG II to activate this same pathway via the AT1-R.33 The precise mechanisms accounting for upregulation of brain RAS in heart failure remain to be determined, but the binding of ALDO to the MR appears to be an important contributing factor.

The present study confirms the previous observation that ALDO in brain tissues of normal rats is almost entirely of adrenal origin, fluctuating in parallel with plasma levels.14 It extends that observation by demonstrating that the close correlation between plasma and brain ALDO concentrations exists in hypothalamus but not in cortex. We can only speculate regarding the reason(s) for the apparent predilection of ALDO for hypothalamic tissue in the HF rats. Early work 12 demonstrated a preferential distribution of labeled ALDO in hypothalamic tissue soon after acute systemic administration, but the relevance of that observation to a persistent high ALDO state like heart failure is not readily apparent. There may be a greater density of ALDO-sensitive MR in the hypothalamus. In a previous study,34 we found a greater expression of mRNA for 11β-hydroxysteroid dehydrogenase type 2 in PVN than in cortex. Another factor may be the dense microvascular network in the PVN region of the hypothalamus,35 facilitating access of circulating ALDO to ALDO-sensitive MR. Receptor density and facilitated access to receptors may assume greater importance when circulating levels of ALDO are high. However, further study will be required to determine the reason(s) for this differential distribution of ALDO in hypothalamic and cortical tissues.

Whatever the mechanism, the association between increased ALDO in hypothalamic tissues, varying in direct proportion to circulating ALDO levels, and increased ACE and AT1-R expression in hypothalamus suggests an important function for blood-borne ALDO in cardiovascular and autonomic regulation. HF rats exhibited increased superoxide (DHE staining) and increased chronic neuronal excitation (Fra-LI activity) diffusely throughout the PVN, involving neurons in both presympathetic and neuroendocrine regions of the PVN. Treatment with the MR antagonist reduced superoxide production and neuronal excitability diffusely throughout the PVN, but with greater effect in parvocellular regions. One may surmise that at least some of the parvocellular PVN neurons influenced by RU28318 were presympathetic, since plasma NE levels also declined with treatment.

A caveat to be considered is that the measurements of LV hemodynamics in this study were made under pentobarbital anesthesia, which is known to reduce sympathetic drive. Since sympathetic responses to stress (e.g., air jet stress) 24 may be exaggerated in heart failure, the overall effect of pentobarbital may have been to minimize the responses of the HF rats, and thus the differences between the HF and sham-operated groups. Nevertheless, mild but significant improvements in LVEDP and LV dP/dt and RV/BW and lung/BW ratios were observed in HF rats treated with RU28318, compared with vehicle treated heart failure rats, suggesting some improvement in left ventricular function. However, these parameters are preload dependent and do not necessarily reflect differences in left ventricular remodeling. Echocardiography, performed under ketamine sedation, revealed no differences in LVEDV, LVEF or % ischemic zone between HF rats treated with RU28318 or vehicle. In a previous study from this laboratory,36 chronic oral administration of another MR antagonist had similar effects, improving volume dependent measures of heart failure without affecting echocardiographic indices of left ventricular remodeling.

Perspectives

The realization that neurochemical changes in the brain lead to autonomic dysfunction in heart failure presents new opportunities and new challenges. In experimental models, central interventions that inhibit ACE activity,7 the binding of ANG II to AT1-R,8 the binding of ALDO to MR,24, 37 and NAD(P)H dependent superoxide production,23 or that quench reactive oxygen species,25 all reduce sympathetic nerve activity. Some of these interventions reduce volume accumulation 7, 37 and left ventricular remodeling,24, 38 likely as a consequence of their effect on sympathetic discharge. Central interventions can be as effective as peripheral interventions with the same agents, but without the undesirable side effects.39 A challenge for the future is how to apply this knowledge. In clinical practice, the brain RAS is not readily accessible to therapeutic intervention. ACE inhibitors,40 AT1-R blockers 41 and MR antagonists may all cross the blood-brain barrier to a greater or lesser extent, but doses sufficient to block central neurochemical mechanisms are unlikely to be achieved without incurring serious adverse side effects – e.g., hypotension, hyperkalemia. A more reasonable approach to the central nervous system abnormalities in heart failure might be to target modifiable peripheral signals, like circulating ALDO, that stimulate the brain RAS. Clinical trials have already demonstrated a beneficial influence of ALDO antagonists in heart failure,42 likely via their effects on peripheral tissues. Agents that modify adrenal synthesis 43 and release of ALDO may confer additional benefit by minimizing the stimulus to central neural activation.

Supplementary Material

Online Supplement

Acknowledgments

SOURCES OF FUNDING This work was supported by a Grant-In-Aid award (#0750164Z) from the American Heart Association Heartland Affiliate (to RBF), a Merit Review award (to RBF) from the Department of Veterans Affairs, an RO1HL073986 (to RBF) from the National Institutes of Health and institutional funds from the University of Iowa

Footnotes

DISCLOSURES None

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