Abstract 383: Depletion of Perivascular Macrophages of the Blood-Brain Barrier Reduces Sympathetic Drive in Rats after Myocardial Infarction
Pro-inflammatory cytokines induce cyclooxygenase-2 (COX-2) activity and synthesis of prostaglandin E2 (PGE2) in perivascular macrophages of hypothalamic paraventricular nucleus (PVN). Cytokine-induced PGE2 synthesis in the brain contributes to increased sympathetic nerve activity following myocardial infarction (MI). Perivascular macrophages can be selectively depleted by clodronate liposomes. Depletion of perivascular macrophages of the blood-brain barrier will reduce COX-2 expression and cytokine-induced sympathetic nerve activity in rats after MI. Clodronate liposomes (CLOD), control liposomes (LIPO) or vehicle (VEH, artificial CSF) were injected (1 μl/min over 40 minutes) into lateral ventricle in rats within 24 hours of MI, or normal rats. One week after injection, perivascular macrophages were completely destroyed and COX-2 immunoreactivity was eliminated in PVN of all CLOD-treated rats but not in LIPO or VEH-treated rats. Activated microglia were unaffected by CLOD. Compared with sham-operated rats (n=10), VEH-treated MI rats (n=11) had increased COX-2 (0.09±0.01* vs 0.05±0.01, normalized to GAPDH, *P<0.05), interleukin-1β (IL-1β, 0.48±0.06* vs 0.21±0.03) and tumor necrosis factor - α (TNF-α, 0.50±0.09* vs 0.22±0.08) mRNA in PVN, IL-1β (23±2* vs 15±1, pg/ml), TNF-α (5±1* vs 2±0, pg/ml), norepinephrine (1146±143* vs 450±66, pg/ml) levels in plasma, PGE2 (1152±109* vs 480±84, pg/ml) in CSF and Fra-like-positive neurons (40±3* vs 21±2) in PVN. CLOD treatment of MI rats (n=11) normalized COX-2 mRNA in PVN and reduced CSF PGE2 (by 30%#, #P<0.05 vs VEH), plasma norepinephrine (by 34%#) and Fra-like positive PVN neurons (by 29%#), but had no effects on IL-1β and TNF-αin PVN or plasma. In normal rats, CLOD treatment (n=9) reduced (P<0.05, vs VEH) sympatho-excitatory responses (renal sympathetic nerve activity, blood pressure and heart rate) induced by intracarotid artery injection of TNF-α (0.5 μg/kg). No effects were found in LIPO-treated MI or normal rats. Pro-inflammatory cytokines stimulate sympathetic excitation after MI by inducing COX-2 activity and PGE2 production in perivascular macrophages of the blood-brain barrier.