88 BRAIN MINERALOCORTICOID RECEPTOR ACTIVATION MEDIATES ARTERIAL PRESSURE ELEVATION THROUGH BRAIN OXIDATIVE STRESS-INDUCED SYMPATHOEXCITATION IN SALT-SENSITIVE AND OBESITY-INDUCED HYPERTENSION

Abstract

Objectives and Background: We have shown previously that sympathoexcitation by brain oxidative stress mediates arterial pressure (AP) elevation in salt-sensitive and obesity-induced hypertension. Sympathoexcitatory roles of brain mineralocorticoid receptor (MR) have been documented, but the detailed mechanisms have not been fully elucidated. We have also shown that MR activation could mediate oxidative stress-induced cardiac and renal dysfunction. Then, we hypothesized that brain MR activation could mediate AP elevation through brain oxidative stress-induced sympathoexcitation. Design and methods: We used high-salt (8%)-loaded Dahl-salt-sensitive rats (Dahl-S) as the salt-sensitive hypertension model, and high-fat (45% kcal as fat)-fed Sprague-Dawley rats as the obesity-induced hypertension model. Sgk-1 and PAI-1 mRNA expression in the isolated hypothalamus was evaluated by real-time quantitative RT-PCR. We examined effects of chronic intracerebroventricular eplerenone on sympathetic nerve activity (response to hexamethonium and urinary norepinephrine) and AP. In Dahl-S, we evaluated the responses of renal sympathetic nerve activity (RSNA) and AP to acute intracerebroventricular administration of tempol, and the hypothalamic oxidative stress level. Results: Salt loading in Dahl-S and fat loading in Sprague-Dawley rats significantly enhanced mRNA expression of Sgk-1 and PAI-1 in the hypothalamus. Intracerebroventricular eplerenone significantly reduced sympathetic nerve activity and AP both in salt-loaded Dahl-S and high-fat-fed rats. Reductions in RSNA and AP values elicited by acute intracerebroventricular tempol, and hypothalamic oxidative stress level were significantly suppressed in intracerebroventricular eplerenone-treated salt-loaded Dahl-S compared with vehicle-treated group. Conclusions: Brain MR activation can be a possible common pathogenic background of AP elevation through brain oxidative stress-induced sympathoexcitation in salt-sensitive and obesity-induced hypertension.