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.

Fig. 1.

Aldosterone and corticosterone contents in hypothalamus of Wistar rats after intracerebroventricular (ICV) infusion of artificial cerebrospinal fluid (aCSF) or Na⁺-rich aCSF combined with ICV infusion of FAD286 (FAD) at 100 μg·kg⁻¹·day⁻¹ or without FAD286 (Veh) for 2 wk. Values are means ± SE (n = 7 or 8/group). *P < 0.05 vs. others.

Fig. 2.

Average 24-h mean arterial pressure (MAP) and heart rate (HR) assessed with telemetry in Wistar rats before and during a 14-day ICV infusion of aCSF or of Na⁺-rich aCSF with FAD286 (100 μg·kg⁻¹·day⁻¹) or without FAD286. Data are means ± SE (n = 4–8/group). *P < 0.05 vs. before infusion. bpm, Beats per minute.

Fig. 3.

Average MAP during day and night in Wistar rats before and during ICV infusion of aCSF or Na⁺-rich aCSF with FAD286 (100 μg·kg⁻¹·day⁻¹) or without FAD286. Data are means ± SE (n = 8/group). Numbers above bars are differences in night vs. day MAP. *P < 0.05 vs. before infusion.**P < 0.05 vs. diurnal variation before infusion. ^aP < 0.05 vs. rats without FAD286 on day 4.

Fig. 4.

Peak increases in renal sympathetic nerve activity (RSNA), MAP, and HR in response to air stress in Wistar rats after ICV infusion of aCSF or Na⁺-rich aCSF with ICV infusion of FAD286 at 100 μg·kg⁻¹·day⁻¹ or without FAD286 (Veh) for 2 wk. Values are means ± SE (n = 7 or 8/group). *P < 0.05 vs. others. ^aP < 0.05 vs. aCSF without ICV FAD286.

Fig. 5.

Changes in RSNA, MAP, and HR in response to changes in MAP in Wistar rats treated with ICV infusion of aCSF or Na⁺-rich aCSF [(Na)aCSF] with ICV infusion of FAD286 at 100 μg·kg⁻¹·day⁻¹ or without FAD286 (Veh) for 2 wk. Values are means ± SE (n = 7 or 8/group) analyzed as a logistic model. *P < 0.05 vs. others. ^aP < 0.05 vs. aCSF with or without ICV FAD286.