Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis

By using an infant rat model of pneumococcal meningitis, we determined whet her endothelins contribute to neuronal damage in this disease. Cerebrospina l fluid analysis demonstrated a significant increase of endothelin-l in inf ected animals compared with uninfected controls. Histopathological examinat ion 24 hours after infection showed brain damage in animals treated with ce ftriaxone alone (median, 9.2% of cortex; range, 0-49.1%). In infected anima ls treated intraperitoneally with the endothelin antagonist bosentan (30 mg /kg, every 12 hours) also, injury was reduced to 0.5% (range, 0-8.6%) of co rtex. Cerebral blood now was reduced in infected animals 6.5 +/- 4.0 ml/min /100 g of brain vs 14.9 +/- 3.1 ml/min/100 g in controls. Treatment with bo sentan restored cerebral blood flow to levels similar to controls (12.8 +/- 5.3 ml/min/100 g). Improved blood flow was not mediated by nitric oxide pr oduction, because bosentan had no effect on cerebrospinal fluid or plasma n itrite/nitrate concentrations at 6, 12, or 18 hours. These data indicate th at endothelins contribute to neuronal injury in this model of pneumococcal meningitis by causing cerebral ischemia.