Increased Cyclooxygenase-2 Expression in Hypothalamic Paraventricular Nucleus in Rats

We investigated the role of nuclear factor B (NFB) in the cytokine-mediated induction of cyclooxygenase-2 activity in the paraventricular nucleus of hypothalamus (PVN), a critical cardiovascular and autonomic center, in rats with heart failure (HF). Sprague–Dawley rats underwent coronary artery ligation to induce HF or sham surgery. HF rats were treated orally for 6 weeks with vehicle (tap water), the NFB inhibitor pyrrolidine dithiocarbamate (150 mg/kg per day), or the mineralocorticoid receptor antagonist eplerenone (30 mg/kg per day), which has been shown to reduce circulating proinflammatory cytokines in this model. Compared with sham surgery, HF rats had higher (P 0.05) levels of aldosterone, interleukin-1 and norepinephrine in plasma and prostaglandin E2 in cerebrospinal fluid. In the PVN, NFB p50 precursor p105 mRNA increased, and mRNA for its inhibitor, I B, decreased (P 0.05). Cyclooxygenase-2 mRNA and protein expression was increased in perivascular cells of the PVN. Both pyrrolidine dithiocarbamate and eplerenone reduced (P 0.05) p105 mRNA and increased I B mRNA in PVN. Both also reduced (P 0.05) cyclooxygenase-2 mRNA and protein expression in PVN, cerebrospinal fluid prostaglandin E2, and plasma norepinephrine. Eplerenone, but not pyrrolidine dithiocarbamate, reduced plasma interleukin-1 . Pyrrolidine dithiocarbamate and eplerenone had no effect on plasma aldosterone. The results suggest that activation of NFB is an intermediary step in cytokine-mediated induction of cyclooxygenase-2 in the PVN of HF rats. By enhancing access of prostaglandin E2 to hypothalamic neurons, this mechanism may contribute to augmented sympathetic nerve activity in HF. (Hypertension. 2007;49:511-518.)