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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

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

¹Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada; and ²Novartis Institutes for BioMedical Research, East Hanover, New Jersey

Submitted 9 April 2008 ; accepted in final form 21 May 2008

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 µg·kg^–1·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 (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.

brain sodium; brain steroids; mineralocorticoid receptor; cytochrome P-450 aldosterone synthase; hypothalamus; sympathoexcitation; diurnal variation

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