Nitric oxide mediates the cerebrovascular and thermoregulatory response to interleukin-1B

INTRODUCTION: Interleukin-1β is an inflammatory cytokine produced in the brain in response to central and systemic infections as well as direct brain insults. Deleterious effects of IL-1β in the brain include upregulation of inflammatory cascades, vasodilation, neurotoxicity and fever. The purpose of this study is to characterize the cerebrovascular and thermoregulatory responses to central injection of IL-1β and to determine the role of nitric oxide (NO) in these responses. We hypothesized that (1) central injection of IL-1β increases cerebral blood flow (CBF), brain and body temperature, and (2) inhibition of NO synthase attenuates the changes in CBF and temperature in response to IL-1β. METHODS: Adult male rats were anesthetized and mechanically ventilated to achieve normal blood gases. CBF was measured in the left cortex by laser-Doppler flowmetry. Normal temperature was maintained with heating lamps and was monitored by thermocouple in rectum and brain cortex. Central injections into the right lateral ventricle (icv) were made over two minutes (min). Three groups were studied: (1) heat-inactivated IL-1β 100 ng icv; (2) IL-1β 100 ng icv; (3) N-nitro-L-arginine methyl ester (L-NAME) 5 mg/kg iv 20 min prior to IL-1β 100 ng icv, followed by L-arginine 150 mg/kg iv (for reversal of L-NAME). RESULTS: Within 15 min of icv injection, IL-1β produced a rapid increase in CBF which persisted for 3 hours. Hyperthermia occurred 45 min after IL-1β and had no apparent effect on CBF. In L-NAME treated rats, CBF and temperature did not change after IL-1β, but temperature increased significantly after reversal with L-arginine. Three hours after injection, IL-1β was localized primarily to glial cells in the pial surfaces by immunocytochemistry. CONCLUSIONS: Central injection of IL-1β causes a rapid and sustained rise in CBF which precedes the increase in temperature. L-NAME completely abolishes both cerebrovascular and thermoregulatory responses to IL-1β. These data suggest that NO mediates the effect of IL-1β on CBF and temperature. Therapies that attenuate NO production in the brain may have clinical utility in patients with acute brain injury.