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Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats

Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada

Submitted 5 January 2006 ; accepted in final form 28 March 2006

Functional studies indicate that the sympathoexcitatory and pressor responses to an increase in cerebrospinal fluid (CSF) [Na⁺] by central infusion of Na⁺-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⁺] by intracerebroventricular infusion of Na⁺-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⁺-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 ¹²⁵I-labeled 351 A and ¹²⁵I-labeled ANG II. When compared with intracerebroventricular aCSF, intracerebroventricular Na⁺-rich aCSF increased CSF [Na⁺] by 5 mmol/l, mean arterial pressure by 20 mmHg, heart rate by 65 beats/min, and hypothalamic content of OLC by 50% and of aldosterone by 33%. Intracerebroventricular spironolactone did not affect CSF [Na⁺] but blocked the Na⁺-rich aCSF-induced increases in blood pressure and heart rate and OLC content. Intracerebroventricular Na⁺-rich aCSF increased ACE and AT₁-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⁺] may increase hypothalamic aldosterone and activate CNS pathways involving MR, and OLC, leading to increases in AT₁-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension.

brain mineralocorticoid receptor; ouabain; angiotensin-converting enzyme; AT₁-receptor

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