Central mineralocorticoid receptor antagonism blocks hypertension in Dahl S/JR rats

Gómez-Sánchez, Elise P.; Fort, C.; Thwaites, D.

doi:10.1152/ajpendo.1992.262.1.e96

Cited by 62 publications

(41 citation statements)

References 27 publications

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“…*P Ͻ 0.05 vs. others. 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.…”

Section: Discussionsupporting

confidence: 90%

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%

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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“…As a result, epithelial Na ϩ channels (ENaC) and Na ϩ -K ϩ -ATPase activity are increased at, e.g., choroid plexus and ventricular ependyma, increasing Na In Dahl S rats, intracerebroventricular infusion of aldosterone elicits the same central nervous system (CNS) phenotype as caused by high dietary salt (1,17,27), including increased brain OLC and decreased responses to intracerebroventricular injection of ouabain as well as sympathetic hyperreactivity, impairment of baroreflex function, and hypertension. Blockade of brain MR prevents the hypertension in Dahl S rats on high salt (10). Intracerebroventricular infusion of a MR antagonist also prevents impairment of baroreflex function and hypertension in spontaneously hypertensive rats (32) and DOCA-salt rats (22).…”

Section: Discussionmentioning

confidence: 93%

“…Stimulation of mineralocorticoid receptors (MR) in the brain contributes to the salt-sensitive hypertension in Dahl S rats, because intracerebroventricular infusion of an MR antagonist prevents hypertension (10). Intracerebroventricular infusion of amiloride or its analog benzamil, which inhibits Na ϩ channels more specifically (24), also prevents salt-induced hypertension in Dahl S rats (12,37) as well as the hypertension induced by intracerebroventricular infusion of aldosterone in normotensive rats (11).…”

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confidence: 99%

Chronic central infusion of aldosterone leads to sympathetic hyperreactivity and hypertension in Dahl S but not Dahl R rats

Huang

Wang

Leenen

2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Chronic central infusion of aldosterone leads to sympathetic hyperreactivity and hypertension in Dahl S but not Dahl R rats. Am J Physiol Heart Circ Physiol 288: H517-H524, 2005. First published September 30, 2004; doi:10.1152/ajpheart.00651.2004.-Six-week-old Dahl saltsensitive (S) and -resistant (R) rats received for 2 wk an intracerebroventricular infusion of aldosterone (Aldo) (22.5 ng/h) or vehicle containing artificial cerebrospinal fluid (aCSF) with 0.15 M Na ϩ . At 8 wk, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in conscious rats at rest, in response to air stress, and to an intracerebroventricular injection of the ␣2-adrenoceptor agonists guanabenz or ouabain. Baroreflex control of RSNA and HR was estimated by using intravenous phenylephrine and nitroprusside. In Dahl S but not Dahl R rats, Aldo raised resting MAP by 20 -25 mmHg, doubled sympathoexcitatory and pressor responses to air stress and sympathoinhibitory and depressor responses to guanabenz, and impaired baroreflex function. In Dahl S but not Dahl R rats, Aldo significantly increased content of ouabainlike compounds (OLC) in the hypothalamus and attenuated excitatory responses to ouabain. Aldo did not affect water intake, plasma electrolytes, or OLC in plasma and adrenal glands. In another set of three groups of Dahl S rats, Aldo dissolved in aCSF containing 0.16, 0.15, or 0.14 M Na ϩ was infused intracerebroventricularly for 2 wk. CSF Na ϩ concentration ([Na ϩ ]) showed only a nonsignificant increase, but resting MAP increased from 111 Ϯ 3 mmHg in rats with Aldo in 0.14 M Na ϩ to 131 Ϯ 3 and 147 Ϯ 3 mmHg with Aldo in 0.15 and 0.16 M Na ϩ , respectively (P Ͻ 0.05 for both). These findings indicate that in Dahl S rats, intracerebroventricular infusion of Aldo causes similar central responses as high salt intake, i.e., increases in brain OLC content, sympathetic hyperreactivity, and hypertension. The extent of the increase in blood pressure (BP) by intracerebroventricular Aldo depends on the [Na ϩ ] in the vehicle. In Dahl R rats, intracerebroventricular Aldo did not increase brain OLC, sympathetic reactivity, and BP, suggesting that in this rat strain, a decrease in central responsiveness to mineralocorticoids may contribute to its salt-resistant nature.ouabain-like compounds; cerebrospinal fluid Na ϩ concentration IN DAHL SALT-SENSITIVE (S) rats, high salt intake increases brain ouabain-like compounds (OLC) (18, 37) followed by activation of the brain renin-angiotensin system (RAS) (20), sympathetic hyperactivity, and hypertension. Stimulation of mineralocorticoid receptors (MR) in the brain contributes to the salt-sensitive hypertension in Dahl S rats, because intracerebroventricular infusion of an MR antagonist prevents hypertension (10). Intracerebroventricular infusion of amiloride or its analog benzamil, which inhibits Na ϩ channels more specifically (24), also prevents salt-induced hypertension in Dahl S rats (12, 37) as well as the hypertension induced by intracere-

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“…The salt-induced hypertension in SS rats is abrogated by the central infusion of mineralocorticoid receptor antagonists, as well as the amiloride analog benzamil, suggesting that aldosterone is acting in the brain in this form of hypertension (11)(12)(13). However, basal plasma levels of aldosterone of the SS rats are normal, much like those of low-renin essential hypertensive patients who respond to anti-mineralocorticoid therapy, for example, spironolactone or triamterene (2).…”

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Is aldosterone synthesized within the rat brain?

Gómez-Sánchez¹,

Ahmad

Romero

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

116

111

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.-Very small amounts of adrenocorticosteroids are synthesized by brain tissue in vitro. While there is evidence suggesting that the synthesis of aldosterone in the brain may have a role in the hypertension of the Dahl salt-sensitive rat, the de novo synthesis of aldosterone or corticosterone within the brain of a living animal has not been demonstrated. We have used sensitive ELISAs to measure aldosterone and corticosterone in the plasma and whole brains of intact rats receiving a normal-, low-, or high-salt diet to alter adrenal aldosterone production and of adrenalectomized rats provided sodium replacement, some of which received aldosterone, corticosterone, or DOC replacement. The results of several experiments were consistent. In intact rats, the brain concentration of aldosterone and corticosterone reflected that in the plasma. However, whereas aldosterone and corticosterone were undetectable or barely undetectable in the plasma of adrenalectomized animals, as was the corticosterone in their brains, aldosterone was consistently found in the brains of adrenalectomized rats, ranging from a mean of 6.6 -41 pg/g, depending on the experiment. Provision of DOC as substrate for the endogenous aldosterone synthase and 11␤-hydroxylase did not significantly increase brain aldosterone or corticosterone content. It is postulated that the small amounts of aldosterone synthesized in the brain could provide a local ligand for autocrine or paracrine activation of the mineralocorticoid receptor.adrenocorticosteroids; aldosterone production; de novo synthesis IT WAS RECOGNIZED OVER 50 YR AGO that steroids acted within the brain (26). Primary among these were metabolites of pregnenolone and progesterone, assumed to be synthesized from circulating steroid precursors. The term "neurosteroids" was coined when new technology allowed the more detailed study of the synthesis and action of these hormones within the brain (15,18,22,23). The complete synthetic enzyme cascade for the synthesis of aldosterone from cholesterol was documented in the brain with the demonstration of mRNA and activity of aldosterone synthase (8,19,20,27). Adrenal corticosteroids, including aldosterone, are synthesized in minute amounts from both endogenous and exogenous tritiated precursors by minces of specific regions of Sprague-Dawley rat brains, including those from adrenalectomized animals (8, 9). However, the amount of these steroids synthesized by brain tissue in vitro is exceedingly small, even when exogenous substrates are provided, and have a negligible contribution to circulating aldosterone and corticosterone levels in the plasma in the adrenalectomized individual.Evidence suggesting that aldosterone synthesis within the brain may be relevant in pathophysiological situations is derived from our studies in the inbred Dahl salt-sensitive (SS) rat. The salt-induced hypertension in SS rats is abrogated by the central infusion of mineralocorticoid receptor antagonists, as well as the amiloride analog benzamil, suggesting that aldosterone is acting in ...

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Central mineralocorticoid receptor antagonism blocks hypertension in Dahl S/JR rats

Cited by 62 publications

References 27 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

Chronic central infusion of aldosterone leads to sympathetic hyperreactivity and hypertension in Dahl S but not Dahl R rats

Is aldosterone synthesized within the rat brain?

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