ENDOTHELIN-B RECEPTOR-MEDIATED INCREASE OF CEREBRAL BLOOD-FLOW IN EXPERIMENTAL PNEUMOCOCCAL MENINGITIS

Study investigates the role of endothelin (ET) receptors in mediating early changes in cerebral blood flow-as measured by laser Doppler flow metry (CBFLDF)-during experimental pneumococcal meningitis. Meningitis was induced with heat-killed pneumococci and confirmed by a significa nt increase in CBFLDF (baseline 100%; 225.3 +/- 21.8% after 6 hours; m ean +/- SD), intracranial pressure (ICP), brain water content, and whi te blood cell count in the CSF. Intravenous administration of the sele ctive endothelin B (ETB) receptor antagonist BQ-788 immediately before pneumococcal challenge (but not 4 hours afterward) significantly atte nuated these pathophysiologic alterations (e.g., CBFLDF 6 hours after pneumococcal challenge: 116.7 +/- 17.4%). Pretreatment with BQ-123, a selective endothelin A receptor antagonist, had no significant effect on ICP and brain water content, but augmented the increase in CBFLDF a nd CSF white blood cell count. Since ET is known to trigger the releas e of nitric oxide (NO) by ETB receptor activation, we examined specifi c ET-NO interactions in primary rat cerebromicrovascular endothelial c ells after stimulation with heat-killed pneumococci. Pneumococci induc ed a significant increase in both ET and NO concentrations in endothel ial cell culture medium. Treatment with phosphoramidon, an inhibitor o f the endothelin-converting enzyme, prevented the production of endoth elin and markedly reduced NO generation. Our data provide evidence tha t ET is involved as a mediator in early pneumococcal meningitis in the rat and contributes to the increase in CBFLDF, ICP, brain water conte nt, and CSF pleocytosis, presumably through ETB receptor-mediated NO p roduction.