Cerebral hyperemia and nitric oxide synthase in rats with ammonia-induced brain edema

Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS).

Male rats received an end-to-side portacaval anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 microM/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210'). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N-omega-nitro-L-arginine (L-NNA, 2 microg/kg per min intravenously)

At 90', brain water was significantly increased (P < 0.015) as compared to the 60' group while CBF was significantly different at 150'. A significant correlation was observed between values of CBF and brain water (r = 0.88, n = 36, P < 0.001). Administration of either TRIM or L-NNA did not prevent the development of cerebral hyperperfu. sion and edema.

We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.