Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension

Wang, Hao; Huang, Bing; Leenen, Frans H. H.

doi:10.1152/ajpheart.00299.2003

Cited by 72 publications

(88 citation statements)

References 32 publications

(45 reference statements)

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“…corticosterone acetate salt-treated rats (33), as well as in Dahl S rats and SHR on high salt intake (14,32). Similar to our previous study (40), in the present study intracerebroventricular infusion of Na ϩ -rich aCSF increased OLC in the hypothalamus. Blockade of MR in the brain by intracerebroventricular infusion of spironolactone prevented this increase.…”

Section: Discussionsupporting

confidence: 90%

“…Indeed, intracerebroventricular infusion of aldosterone at low rates increases brain OLC and blood pressure (BP) (12,23), particularly when combined with small increases in CSF [Na ϩ ] (23). Blockade of brain OLC prevents intracerebroventricular aldosterone-induced sympathetic hyperactivity and hypertension (40). Increasing CSF [Na ϩ ] by intracerebroventricular infusion of Na ϩ -rich artificial CSF (aCSF) elicits sympathoexcitatory and pressor responses in a number of rat strains (21,22,25,38).…”

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confidence: 99%

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Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Huang

Cheung²,

Wang³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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tional studies indicate that the sympathoexcitatory and pressor responses to an increase in cerebrospinal fluid (CSF) [Na ϩ ] by central infusion of Na ϩ -rich artificial cerebrospinal fluid (aCSF) in Wistar rats are mediated in the brain by mineralocorticoid receptor (MR) activation, ouabain-like compounds (OLC), and AT1-receptor stimulation. In the present study, we examined whether increasing CSF [Na ϩ ] by intracerebroventricular infusion of Na ϩ -rich aCSF activates MR and thereby increases OLC and components of the renin-angiotensin system in the brain. Male Wistar rats received via osmotic minipump an intracerebroventricular infusion of aCSF or Na ϩ -rich aCSF, in some groups combined with intracerebroventricular infusion of spironolactone (100 ng/h), antibody Fab fragments (to bind OLC), or as control ␥-globulins. After 2 wk of infusion, resting blood pressure and heart rate were recorded, OLC and aldosterone content in the hypothalamus were assessed by a specific ELISA or radioimmunoassay, and angiotensin-converting enzyme (ACE) and AT1-receptor binding densities in various brain nuclei were measured by autoradiography using 125 I-labeled 351 A and 125 I-labeled ANG II. When compared with intracerebroventricular aCSF, intracerebroventricular Na ϩ -rich aCSF increased CSF [Na ϩ ] by ϳ5 mmol/l, mean arterial pressure by ϳ20 mmHg, heart rate by ϳ65 beats/min, and hypothalamic content of OLC by 50% and of aldosterone by 33%. Intracerebroventricular spironolactone did not affect CSF [Na ϩ ] but blocked the Na ϩ -rich aCSF-induced increases in blood pressure and heart rate and OLC content. Intracerebroventricular Na ϩ -rich aCSF increased ACE and AT 1-receptor-binding densities in several brain nuclei, and Fab fragments blocked these increases. These data indicate that in Wistar rats, a chronic increase in CSF [Na ϩ ] may increase hypothalamic aldosterone and activate CNS pathways involving MR, and OLC, leading to increases in AT 1-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension. brain mineralocorticoid receptor; ouabain; angiotensin-converting enzyme; AT 1-receptor NEURAL MECHANISMS play a major role in the development of salt-induced hypertension in Dahl salt-sensitive (S) rats (3). In Dahl S rats but not salt-resistant (R) rats, high salt intake increases cerebrospinal fluid (CSF) [Na ϩ ] (20), associated with increases in hypothalamic ouabain-like compounds (OLC) (41) and in angiotensin-converting enzyme (ACE) activity (46) and AT 1 -receptors (44). Functional studies indicate that high saltinduced sympathetic hyperactivity and hypertension can be prevented by CNS blockade of aldosterone synthesis (15), mineralocorticoid receptors (MR) (14, 32), epithelial sodium channels (ENaC) (42), OLC, or of AT 1 -receptors (19). We proposed (23) that in Dahl S rats on high salt, genetically determined enhancement in the activity of MR-ENaC activates central pathways involving OLC and AT 1 -receptors resulting in sympathetic hyperactivity and hypertension.Recent studies...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Huang

Cheung²,

Wang³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…It has also been reported that central administration of aldosterone appears to depend on the MR-ENaC-ouabain pathway and, ultimately, AT 1 receptor stimulation. 37 The sympathoexcitatory and pressor responses to central infusion of aldosterone and Na + -rich aCSF can be prevented by central infusion of the sodium channel blocker benzamil or an ouabain blocker, 27,38 and the pressor responses elicited by central infusion of aldosterone or ouabain can be blocked by an AT 1 blocker. 27,39 In the RVLM, microinjection of an ouabain-like compound 40 or angiotensin II 21 elicits a pressor response and sympathoexcitation.…”

Section: Discussionmentioning

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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“…According to previous reports, 36,39 aldosterone in the brain causes ouabain production and oxidative stress, which in turn stimulates sympathetic outflow in the central nervous system. Our results suggest that aldosterone depolarized bulbospinal RVLM neurons directly and that ENaCs are involved in this action.…”

Section: Effect Of Enac On Bulbospinal Neurons In the Rvlmmentioning

confidence: 95%

“…22,34,35 Wang et al 36 showed the presence of ENaC in the choroid plexus and the ependyma of the anteroventral third ventricle, and reported that intracerebroventricular infusion of aldosterone increased blood pressure and intracerebroventricular infusion of benzamil blocked this increase. To our knowledge, there are no reports that have indicated the existence of ENaCs in bulbospinal RVLM neurons.…”

Section: Effect Of Enac On Bulbospinal Neurons In the Rvlmmentioning

confidence: 99%

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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Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension

Cited by 72 publications

References 32 publications

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

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

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

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