Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital.
OBJECTIVE
The aim was to determine the effect of ammonia (NH(3)) 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 NH(3) and LPS.


METHODS
In experiment A, four groups of rats received ammonium acetate (140 micromol/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-alpha), 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 NH(3) 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-alpha concentration.


CONCLUSIONS
In rats anaesthetised with pentobarbital NH(3) 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 NH(3) and LPS seems mediated by other amiloride-sensitive-ion-pathways in the BBB than the Na(+)/H(+) exchanger.
Pedersen
Hans R
HR
Department of Hepatology, Rigshospitalet, Section A-2121, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark.
Ring-Larsen
Helmer
H
Olsen
Niels Vidiendal
NV
Larsen
Fin Stolze
FS
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000641:Ammonia / Q000097:blood / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004357:Drug Synergism; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D022124:Hyperammonemia / Q000378:metabolism / Q000503:physiopathology*; D007427:Intracranial Pressure / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009994:Osmolar Concentration; D010424:Pentobarbital; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D008070:Lipopolysaccharides; D026941:Sodium Channel Blockers; D017923:Sodium-Hydrogen Exchangers; D014409:Tumor Necrosis Factor-alpha; D005973:Glutamine; D018698:Glutamic Acid; D000641:Ammonia; D000584:Amiloride; C056369:5-(N-methyl-N-isobutyl)amiloride; D010424:Pentobarbital