Abstract 1596: Central Infusion of Aldosterone Upregulates the Brain Renin-angiotensin System and Increases Oxidative Stress and Sympathetic Nerve Activity
Introduction: Aldosterone (ALDO) exerts important effects on the cardiovascular system via several different mechanisms. ALDO acts upon mineralocorticoid receptors (MR) in the brain to regulate sympathetic drive, but the mechanism are still poorly understood. In peripheral tissues, ALDO can upregulate renin-angiotensin system (RAS).
Hypothesis: Central ALDO increases sympathetic nerve activity by upregulating activity of the brain RAS.
Methods: Sprague-Dawley rats were implanted with two intracerebroventricular (ICV) cannulas. Aldoste-rone (22.5 ng/hr) or vehicle (Veh) was infused via one cannula and the selective MR antagonist RU28318 (1 μg/hr) or Veh was infused via the other. Mean arterial pressure (MAP) and heart rate (HR) were measured via an implanted arterial cannula. After a week of continuous ICV infusion of drug or vehicle, rats were sacrificed to obtain blood and brain tissue for real time PCR and immunohistochemistry.
Results: ICV infusion of ALDO (n=5) increased (*p<0.05, vs Veh, n=4) MAP (14 ± 3 mmHg*) and HR (28 ± 5 bpm*). These effects were prevented by concomitant infusion of RU28318 (n=5). ALDO increased hypothalamic angiotensin type 1 receptor (AT1-R, 117%*) and angiotensin converting enzyme (ACE, 34%*) mRNA. Concomitant treatment with RU28318 reduced (†p < 0.05 vs ALDO+Veh, n=4) hypothalamic AT1R (51%) and ACE (11%†) mRNA. Immunohistochemistry revealed increased (#p<0.05) ACE (67%#, intensity of fluorescence) and AT1-R (59%#) protein expression and dihydroethidium (DHE, indicating oxidative stress) staining (224%#) in the hypothalamic paraventricular nucleus following ALDO (n=4) infusion compared with Veh (n=3). These effects were reduced (§ p<0.05, vs Veh+ALDO) by concomitant infusion of the MR antagonist RU28318 (n=4): ACE (7%§); AT1-R (5%§) and DHE (29%§). ALDO infusion increased (p<0.05 ALDO vs Veh, n+6) plasma norepinephrine (NE, a surrogate indicator for sympathetic nerve activity) levels (pg/ml) (256 ± 10 vs 187 ± 10). Coadministration of RU28318 (n=6) blunted (p < 0.05) the NE response (215 ± 8).
Conclusion: Central aldosterone, acting upon brain MR, increases key elements of RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms.