Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction

Huang, Bing; White, Roselyn; Ahmad, Monir; Tan, Junhui; Jeng, Arco Y.; Leenen, Frans H. H.

doi:10.1093/cvr/cvn222

Cited by 29 publications

(37 citation statements)

References 19 publications

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“…Together, these findings indicate that ICV FAD286, indeed, causes specific blockade of the aldosterone synthase enzyme in the CNS. Similar to our previous studies in Wistar rats (21,22), ICV FAD286 did not decrease hypothalamic aldosterone to levels lower than in rats with regular salt intake. These findings may indicate the presence of two pools of aldosterone in the hypothalamus, one locally produced in the brain and one reflecting uptake from the circulation.…”

Section: Discussionsupporting

confidence: 91%

“…The doses of FAD286 were initially extrapolated from studies using oral FAD286 (8,25). ICV infusion of FAD286 at a rate of 100 g ⅐ kg Ϫ1 ⅐ day Ϫ1 showed marked inhibitory responses in rats with ICV infusion of Na ϩ -rich aCSF (21) and in rats after myocardial infarction (22). The ICV dose of spironolactone was adopted from previous studies (9,23) and is markedly lower than orally active doses (23).…”

Section: Experimental Protocolmentioning

confidence: 99%

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Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

Huang¹,

White²,

Jeng³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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) and blood pressure (BP). Intracerebroventricular (ICV) infusion of a mineralocorticoid receptor (MR) blocker prevents the hypertension. To assess the role of aldosterone locally produced in the brain, we evaluated the effects of chronic central blockade with the aldosterone synthase inhibitor FAD286 and the MR blocker spironolactone on changes in aldosterone and corticosterone content in the hypothalamus and the increase in CSF [Na ϩ ] and hypertension induced by high salt intake in Dahl S rats. After 4 wk of high salt intake, plasma aldosterone and corticosterone were not changed, but hypothalamic aldosterone increased by ϳ35% and corticosterone tended to increase in Dahl S rats, whereas both steroids decreased by ϳ65% in Dahl salt-resistant rats. In Dahl S rats fed the high-salt diet, ICV infusion of FAD286 or spironolactone did not affect the increase in CSF [Na ϩ ]. ICV infusion of FAD286 prevented the increase in hypothalamic aldosterone and 30 mmHg of the 50-mmHg BP increase induced by high salt intake. ICV infusion of spironolactone fully prevented the salt-induced hypertension. These results suggest that, in Dahl S rats, high salt intake increases aldosterone synthesis in the hypothalamus and aldosterone acts as the main MR agonist activating central pathways contributing to salt-induced hypertension.brain; corticosterone; high-salt diet IN DAHL SALT-SENSITIVE (S) rats, high salt intake increases cerebrospinal fluid (CSF) Na ϩ concentration ([Na ϩ ]) and causes sympathetic hyperactivity and hypertension (19). Saltinduced sympathetic hyperactivity and hypertension can be prevented by central blockade of steroid biosynthesis by the steroid synthase 3␤-hydroxysteroid dehydrogenase (HSD) inhibitor trilostane (14) or central blockade of mineralocorticoid receptors (MR) (13).The agonist binding to the MR in the central nervous system (CNS) has not been defined, nor has its origin, i.e., whether it is derived from the circulation or locally produced, been determined. Inasmuch as central infusion of trilostane has antihypertensive effects (14), it appears that local production of a steroid in the CNS plays a major role. However, trilostane blocks the synthesis not only of the mineralocorticoid hormone aldosterone but also of the glucocorticoid hormone corticosterone (14, 24). Aldosterone and corticosterone can be synthesized in the brain (11,12,24). Aldosterone and corticosterone bind MR with equal affinity (3), but the presence of the corticosterone-inactivating enzyme 11␤-HSD-2 enhances aldosterone selectivity of the MR in brain regions where it is expressed, such as the paraventricular nucleus of the hypothalamus (34).There is no evidence that, in Dahl S rats, high salt intake actually increases aldosterone or corticosterone production and release in brain regions implicated in sympathetic regulation or, alternatively, causes changes in MR or 11␤-HSD-2 expression. FAD286 is a specific aldosterone synthase (CYP11B2) blocker that appears to have no effects on corticosterone synthesis (25). Oral administration...

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Section: Discussionsupporting

confidence: 91%

Section: Experimental Protocolmentioning

confidence: 99%

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

Huang¹,

White²,

Jeng³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In a previous study, Connell et al 1 showed that the central nervous system can produce aldosterone. Furthermore, using FAD286, Gomez-Sanchez et al 2 and Hung et al 6,7 proved that aldosterone is synthesized in the brain. Kumar et al 4 demonstrated the presence of aldosterone-related mRNA species in the RVLM.…”

Section: Effect Of Fad286 On Bulbospinal Neurons In the Rvlmmentioning

confidence: 99%

“…4 Furthermore, aldosterone is involved in remodeling after myocardial infarction, and central blockade of aldosterone has been shown to attenuate cardiac remodeling. 5,6 Recent studies have demonstrated the existence of an aldosterone system in the brain, 4 and an increase in [Na þ ] in cerebrospinal fluid (CSF) has been shown to increase aldosterone biosynthesis. 7 Although the mechanism was unknown, Zhang et al 3 demonstrated that aldosterone upregulated key elements (angiotensin II type 1 receptor and angiotensin-converting enzyme in the brain reninangiotensin system) and induced oxidative stress in the hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

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Aldosterone is synthesized in and activates bulbospinal neurons through mineralocorticoid receptors and ENaCs in the RVLM

et al. 2013

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The effects of aldosterone and mineralocorticoid receptor (MR) blockers on presympathetic neurons in the rostral ventrolateral medulla (RVLM) are well studied. To directly investigate whether aldosterone, eplerenone (an MR blocker), FAD286 (an aldosterone synthase inhibitor) and benzamil (an epithelial sodium channel (ENaC) blocker) affect RVLM neurons, we examined changes in the membrane potentials (MPs) of bulbospinal RVLM neurons using the whole-cell patch-clamp technique during superfusion with these drugs to brainstem-spinal cord preparations. Aldosterone superfusion (0.1 lmol/l) depolarized the RVLM neurons. In contrast, eplerenone superfusion (1 lmol/l) hyperpolarized them. To evaluate the existence of aldosterone, FAD286 superfusion (10 lmol/l) was performed, and the RVLM neurons became hyperpolarized during FAD superfusion. These data suggest that MRs exist and that aldosterone is synthesized in the brainstem. Benzamil superfusion (1 lmol/l) hyperpolarized the RVLM neurons. To clarify whether aldosterone, eplerenone, FAD286 and benzamil acted directly on the RVLM neurons, a lowCa 2 þ , high-Mg 2 þ solution was used to block the synaptic input to the RVLM neurons, and the above-mentioned drugs were added during the low-Ca 2 þ superfusion. During the aldosterone superfusion, the RVLM neurons became depolarized, and they became hyperpolarized during eplerenone, FAD286 or benzamil superfusion. Importantly, when aldosterone was superfused after the benzamil solution, the MPs of the RVLM neurons did not depolarize. These results suggest that MRs are present in the RVLM neurons and that aldosterone is synthesized in the RVLM. The RVLM neurons themselves possess ENaCs, and ENaCs are the underlying mechanism by which aldosterone activates RVLM neurons. Hypertension Research (2013) 36, 504-512; doi:10.1038/hr.2012.224; published online 31 January 2013Keywords: aldosterone; benzamil; FAD286; RVLM neurons; whole-cell patch clamp INTRODUCTIONThe actions of aldosterone include vasoconstriction, vascular fibrosis, endothelial dysfunction, and sodium reabsorption and retention. These actions contribute to hypertension. However, recently, many studies have demonstrated the relationship between aldosterone and sympathetic nerve activity. In fact, aldosterone has been shown to cross the blood-brain barrier relatively easily, 1 as clarified using the model developed by Gomez-Sanchez et al. 2 showed that the intracerebroventricular infusion of antagonists of the mineralocorticoid receptor (MR), at a dose that had no effect systemically, lowered blood pressure. Intracerebroventricular infusion of aldosterone increased blood pressure, 3 and MRs were found in the brain. 4 Furthermore, aldosterone is involved in remodeling after myocardial infarction, and central blockade of aldosterone has been shown to attenuate cardiac remodeling. 5,6 Recent studies have demonstrated the existence of an aldosterone system in the brain, 4 and an increase in [Na þ ] in cerebrospinal fluid

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Aldosterone Inhibition and Cardiovascular Protection: More Important Than it Once Appeared

Martínez

2010

Cardiovasc Drugs Ther

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Aldosterone is present and active all along the cardiovascular continuum. Excessive tissue production occurs in cardiovascular diseases including myocardial infarction (MI) and heart failure, resulting in a multitude of adverse effects in the cardiovascular system necessitating pharmacologic blockade of this neurohormone. Both human and animal studies have consistently proven the beneficial effects of antialdosteronics in the improvement of: 1) endothelial function, 2) modulation of inflammatory mechanisms between blood and the vascular wall and 3) reduction of tissue proliferation and cardiovascular remodeling leading to different severities of cardiovascular damage. These basic mechanisms of anti-aldosterone therapy strongly support the promising data observed in major clinical trials with aldosterone blockers in cardiovascular diseases, specially in heart failure patients. Whereas aldosterone receptor blockers were initially viewed as potassium-sparing diuretics there has been a clear change of concept in the past 10 years, mainly following the positive results of RALES with spironolactone in chronic heart failure, followed by EPHESUS using eplerenone in patients with systolic dysfunction post MI. The significant positive results in both studies were a clear support for the inclusion of this pharmacologic intervention as first line treatment in most international guidelines for the management of heart failure. More recent and ongoing studies are exploring the usefulness of this type of intervention in preventing vascular and myocardial hypertrophy and remodeling in refractory hypertensive and some hyperfibrotic syndromes. There are also provocative studies investigating in the possibility of inhibiting atherosclerosis. More recently, some studies are suggesting the benefit of aldosterone blockade in sleep apnea. In addition, two large multicentric trials, TOPCAT and EMPHASIS are analyzing the potential use of antialdosteronics in patients with cardiac insufficiency and preserved systolic function and the possibility of extending their indication in systolic heart failure to Phase II respectively. New compounds, blocking the synthesis of aldosterone instead of blocking its receptor are being developed, and initial Phase 2 studies are positive. All of the above results are very interesting, show an optimistic future and are consolidating and enlarging the spectrum of aldosterone blockade in cardiovascular disorders every day.

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Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction

Abstract: These data suggest that aldosterone produced locally in the brain acts as the main agonist of mineralocorticoid receptors in the CNS and contributes substantially to the progressive heart failure post MI.

Cited by 29 publications

References 19 publications

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats

Aldosterone is synthesized in and activates bulbospinal neurons through mineralocorticoid receptors and ENaCs in the RVLM

Aldosterone Inhibition and Cardiovascular Protection: More Important Than it Once Appeared

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