Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide.
Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism and that some of these changes occur via the nitric oxide pathway.
Tureen
J
J
Department of Pediatrics, University of California San Francisco 94143.
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D005260:Female; D006801:Humans; D007773:Lactates / Q000134:cerebrospinal fluid*; D019344:Lactic Acid; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
D007773:Lactates; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019344:Lactic Acid