Central infusion of aldosterone synthase inhibitor prevents sympathetic hyperactivity and hypertension by central Na⁺ in Wistar rats

Abstract

In Wistar rats, increasing cerebrospinal fluid (CSF) Na+ concentration ([Na+]) by intracerebroventricular (ICV) infusion of hypertonic saline causes sympathetic hyperactivity and hypertension that can be prevented by blockade of brain mineralocorticoid receptors (MR). To assess the role of aldosterone produced locally in the brain in the activation of MR in the central nervous system (CNS), Wistar rats were infused ICV with artificial CSF (aCSF), Na+ -rich (800 mmol/l) aCSF, aCSF plus the aldosterone synthase inhibitor FAD286 (100 microg x kg(-1) x day(-1)), or Na+ -rich aCSF plus FAD286. After 2 wk of infusion, rats treated with Na+ -rich aCSF exhibited significant increases in aldosterone and corticosterone content in the hypothalamus but not in the hippocampus, as well as increases in resting blood pressure (BP) and sympathoexcitatory responses to air stress, and impairment of arterial baroreflex function. Concomitant ICV infusion of FAD286 prevented the Na+ -induced increase in hypothalamic aldosterone but not corticosterone and prevented most of the increases in resting BP and sympathoexcitatory and pressor responses to air stress and the baroreflex impairment. FAD286 had no effects in rats infused with ICV aCSF. In another set of rats, 24-h BP and heart rate were recorded via telemetry before and during a 14-day ICV infusion of Na+ -rich aCSF with or without FAD286. Na+ -rich aCSF without FAD286 caused sustained increases ( approximately 10 mmHg) in resting mean arterial pressure that were absent in the rats treated with FAD286. These data suggest that in Wistar rats, an increase in CSF [Na+] may increase the biosynthesis of corticosterone and aldosterone in the hypothalamus, and mainly aldosterone activates MR in the CNS leading to sympathetic hyperactivity and hypertension.

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

“…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.…”

“…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. They suggested that aldosterone increased sympathetic nerve activity through those mechanisms.…”

Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats

“…The sympathoexcitatory and hypertensive responses to intracerebroventricular infusion of Na ϩ -rich aCSF or ouabain can also be inhibited by intracerebroventricular losartan (13). Altogether, these results suggest that in response to a chronic increase in CSF [Na ϩ ], increased binding of an endogenous agonist (presumably aldosterone) (15) to MRs mediates the activation of benzamil-blockable Na ϩ influx, leading to "ouabain" release and ANG II type 1 (AT 1 ) receptor stimulation. Where and how in the CNS these mechanisms interact have not yet been studied.…”

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).…”