Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital

Background/Aims: The aim was to determine the effect of ammonia (NH3) and lipopolysaccharide (LPS) alone or in combination, on cerebral blood flow (CBF) and intracranial pressure (ICP) in the rat. Since amiloride-sensitive-ion-pathways in the blood-brain barrier (BBB) modulate CBF, we also aimed to test if Na+/H+-inhibitors could prevent this possible synergism between NH3 and LPS. Methods: In experiment A, four groups of rats received ammonium acetate (140 mu mol/kg/min) or saline, each of them associated with either vehicle or LPS (2 mg/kg). In experiments B and C, rats received similar treatments after having received amiloride (30 mg/kg) or 5-(N-methyl-N-isobutyl)-amiloride (MIA, 5 mg/kg). Plasma tumor-necrosis-factor-alpha (TNF-a), ICP (via a cisterna magna catheter) and CBF (by laser-Doppler flowmetry) were measured. Results: An increase in ICP and CBF within 60 min was observed only in rats that received NH3 together with LPS as compared to any other group (P < 0.01), which could be prevented by amiloride (P < 0.05), but not by MIA. Both amiloride and MIA decreased the plasma TNF-a concentration. Conclusions: In rats anaesthetised with pentobarbital NH3 infusion aggravates a LPS induced rise in ICP and induces an increase in CBF less clearly seen with LPS alone. This effect is prevented by the non-specific Na+/H+ inhibitor amiloride, but not by MIA, a specific inhibitor of Na+/H+ exchanger. Thus, the synergistic effect of NH3 and LPS seems mediated by other amiloride-sensitive-ion-pathways in the BBB than the Na+/H+ exchanger. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.