Effects of eplerenone, a selective mineralocorticoid receptor antagonist, on clinical and experimental salt-sensitive hypertension

Takeda, Yoshiyu

doi:10.1038/hr.2009.29

Cited by 29 publications

(15 citation statements)

References 33 publications

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“…4,5 The beneficial effects of the MR antagonist spironolactone or the more specific antagonist eplerenone on end-organ damage have been studied in animal models. [6][7][8][9][10] It has been reported that MRs regulate epithelial Na channels (ENaCs) that are important for the regulation of sodium transport and the maintenance of extracellular fluid volume and arterial pressure (AP) in the kidney. 11 Recent studies have reported the distribution of MRs or ENaCs in the choroid plexus, ependyma and neurons, such as those in the supraoptic nucleus, paraventricular nucleus and nucleus tractus solitarius.…”

Section: Introductionmentioning

confidence: 99%

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

et al. 2012

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Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na + -rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serumand glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na + -rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na + -rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP.

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Section: Introductionmentioning

confidence: 99%

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

et al. 2012

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“…[9][10][11] In keeping with the pathophysiological roles, aldosteronism and oxidative stress are salutary responses to mineralocorticoid receptor antagonism. [12][13][14][15][16] AN EXPERIMENTAL MODEL OF ALDOSTERONISM Aldosterone/salt treatment We have worked extensively with the ALDOST model, wherein eightweek-old male Sprague-Dawley rats are first uninephrectomized to reduce renal mass available for Na + excretion. An osmotic minipump filled with ALDO is implanted subcutaneously; it releases ALDO (0.75 mg h À1 ) to raise PAC to levels found in patients with congestive heart failure, whereas drinking water is fortified with 1% NaCl to create inappropriate aldosteronism and 0.4% KCl to prevent hypokalemia and associated cardiac pathology.…”

Section: Aldosteronism Defined and Stimuli That Regulate Adrenal Aldomentioning

confidence: 99%

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

et al. 2010

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Inappropriately (relative to dietary Na + ) elevated plasma aldosterone concentrations (PAC), or aldosteronism, have been incriminated in both the appearance of the cardiometabolic syndrome (CMS) and its progressive nature. The deleterious dual consequences of elevated PAC and dietary Na + have been linked to several components of the CMS, including salt-sensitive hypertension. Moreover, their adverse consequences are considered to be synergistic, culminating in a pro-oxidant phenotype with oxidative injury involving the heart and systemic tissues, including peripheral blood mononuclear cells (PBMC). Our experimental studies in rats receiving aldosterone/salt treatment have identified a common pathogenic event that links aldosteronism to the induction of oxidative stress. Herein, we review these findings and the important role of excessive intracellular Ca 2+ accumulation (EICA), or intracellular Ca 2+ overloading, which occurs in the heart and PBMC, leading to, respectively, cardiomyocyte necrosis with a replacement fibrosis and an immunostimulatory state with consequent coronary vasculopathy. The origin of EICA is based on elevations in plasma parathyroid hormone, which are integral to the genesis of secondary hyperparathyroidism that accompanies aldosteronism and occurs in response to plasma-ionized hypocalcemia and hypomagnesemia whose appearance is the consequence of marked urinary and fecal excretory losses of Ca 2+ and Mg 2+ . In addition, we found intracellular Ca 2+ overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn 2+ , which together regulate the redox state of cardiac myocytes and mitochondria via the induction of oxidative stress and generation of antioxidant defenses, respectively. To validate our hypothesis, a series of site-directed, sequential pharmacological and/or nutriceutical interventions targeted along cellular-molecular cascades were carried out to either block downstream events leading to the pro-oxidant phenotype or to enhance antioxidant defenses. In each case, the interventions were found to be cardioprotective. These cumulative salutary responses raise the prospect that pharmacological agents and nutriceuticals capable of influencing extra-and intracellular Ca 2+ and Zn 2+ equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism.

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“…This may explain why microinjection of eplerenone into the NTS reversed the baroreflex sensitivity induced by the high sodium load. Indeed, eplerenone exhibits a potential antihypertensive effect with a slightly different profile from that of spironolactone, and eplerenone is effective against salt-sensitive hypertension (15). It is also possible that a high sodium load may have altered the activity of HSD2, resulting in a change of the balance between aldosterone and corticosterone production.…”

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confidence: 99%

Aldosterone-Sensitive Nucleus Tractus Solitarius Neurons Regulate Sensitivity of the Baroreceptor Reflex in High Sodium–Loaded Rats

Masuda¹,

Hirabara²,

Nakamura³

et al. 2010

J Pharmacol Sci

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Baroreceptor and chemoreceptor signals are transmitted to the nucleus tractus solitarius (NTS) via the primary afferent fibers of the glossopharyngeal and vagal nerves, suggesting a role for the NTS in modulating the arterial baroreceptor reflex (baroreflex). The NTS contains numerous neurotransmitters and receptors, including glutamate, GABA, or substance P (1). However, the role of these neurotransmitters in regulatory baroreceptor and chemoreceptor signals is not fully understood. Recently, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD2) and the mineralocorticoid receptors (MR) were identified in the NTS along with common neurotransmitters; such neurons are termed 'aldosterone-sensitive HSD2 neurons' (2 -5). Furthermore, a number of studies have shown that the aldosterone-sensitive HSD2 neurons in the NTS are involved in sodium appetite or in regulation of body fluid circulation as they are selectively activated by sodium deficiency (2, 4).Aldosterone is secreted from the adrenal cortex in response to sodium deficiency and also amplifies sodium intake. A cardiovascular role for aldosterone has been suggested from the evidence of MR expression in vascular tissues, including the heart. Furthermore, some studies have reported a role for aldosterone in the baroreflex response. For example, both acute and chronic peripheral aldosterone administration impaired baroreceptor responses in dogs (6) and in humans (7). In addition, central infusion of sodium-enriched artificial cerebrospinal fluid (aCSF) caused increased aldosterone and corticosterone levels in the hypothalamus and impaired baroreceptor function (8, 9), suggesting a role for central aldosterone in baroreflex function. However, the role of aldosteronesensitive neurons in the NTS in baroreflex responses remains unclear.In the present study, we tested the hypothesis that the aldosterone-sensitive neurons in the NTS regulate the baroreflex function. To address this hypothesis, we examined the baroreflex sensitivity induced by phenylephrine in high sodium-loaded rats.Male Wistar rats (180 -200 g) were purchased from Kyudo (Kumamoto). The animals were maintained at 24 ± 2°C with a 12-h light-dark cycle (light on at 07:00 Medicine, Kyoto 602-8566, Japan Received December 25, 2009; Accepted February 19, 2010 Abstract. We examined the role of aldosterone-sensitive neurons in the nucleus tractus solitarius (NTS) in the arterial baroreceptor reflex (baroreflex) function. Baroreflex sensitivity was induced by phenylephrine in high sodium-loaded rats and was significantly reduced. This baroreflex sensitivity was reversed by microinjection of the mineralocorticoid receptor (MR) antagonist eplerenone into the NTS. 11β-Hydroxysteroid dehydrogenase type 2 neurons and MR were also identified in the NTS. These data suggest that the aldosterone-sensitive neurons in the NTS may have an important role in baroreflex function.

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Effects of eplerenone, a selective mineralocorticoid receptor antagonist, on clinical and experimental salt-sensitive hypertension

Cited by 29 publications

References 33 publications

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

Aldosterone-Sensitive Nucleus Tractus Solitarius Neurons Regulate Sensitivity of the Baroreceptor Reflex in High Sodium–Loaded Rats

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