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

Abstract

) 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...

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

“…30 The blockade of MRs in the brain has been suggested to decrease sympathetic nerve activation and result in a decrease in the blood pressure rise from high salt intake in saltsensitive rats. 28 This decrease has also been associated with an improvement in the cardiac function of mice with pressure overload. 30 In the present study, we confirmed that endogenous blockade of MRs in the RVLM decreased blood pressure via sympathoinhibition, with greater decreases in SHRSPs.…”

“…MRs in the brain have been shown to be involved in sympathetic nerve activation in salt-sensitive hypertensive rats, 28 in a rat model of myocardial infarction 29 and in other saltsensitive models. 30 The blockade of MRs in the brain has been suggested to decrease sympathetic nerve activation and result in a decrease in the blood pressure rise from high salt intake in saltsensitive rats.…”

Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease

“…ICV aldosterone synthase inhibitor, as well as a mineralocorticoid receptor blocker, can prevent salt-induced hypertension in Dahl salt-sensitive rats. 46 The blockade of central mineralocorticoid receptors also improved saltinduced left-ventricular systolic dysfunction through attenuation of sympathoexcitation in pressure-overload model mice. 47 Thus, aldosterone and mineralocorticoid receptors may contribute to the overproduction of central oxidative stress overproduction, resulting in sympathoexcitationinduced hypertension.…”

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

“…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 fact, central infusion of sodium-rich artificial CSF increased aldosterone content in the hypothalamus, suggesting that high sodium levels may cause region-specific aldosterone synthesis (8,9). Increased sodium can also cause impairment of the baroreflex function (8,9).…”