MODULATION OF BASAL AND POSTISCHEMIC LEUKOCYTE-ENDOTHELIAL ADHERENCE BY NITRIC-OXIDE

Background and Purpose-Recent studies indicate that leukocytes are imp ortant contributors to secondary vascular and parenchymal injury after cerebral ischemia, The present study was undertaken to define nitric oxide (NO)-based mechanisms that regulate leukocyte-endothelial intera ctions in the cerebral vasculature, how these mechanisms are affected by cerebral ischemia, and whether NO-based therapies can affect postis chemic leukocyte dynamics. Methods-Leukocyte adherence to pial venules of anesthetized newborn piglets was quantified by in situ fluorescenc e videomicroscopy through closed cranial windows during basal conditio ns and during reperfusion after 9 minutes of asphyxia. Nitric oxide sy nthase (NOS) was inhibited by local window superfusion of L-nitroargin ine; superfusion of sodium nitroprusside was used to donate NO. Result s-Local inhibition of NOS under resting conditions increased leukocyte -endothelial adherence 2.2-fold and 3.9-fold over baseline values afte r 1 hour and 2 hours, respectively; this response was completely block ed by cosuperfusion with L-arginine. Cosuperfusion of superoxide dismu tase reversed L-nitroarginine-induced leukocyte adherence by 89% and 6 3% at these respective time points. The extent of acute leukocyte adhe rence elicited by NOS inhibition was similar in magnitude to that obse rved during the initial 2 hours of reperfusion after asphyxia. Leukocy te adherence was not additionally increased in asphyxic animals treate d with L-nitroarginine. Sodium nitroprusside robustly inhibited asphyx ia-induced leukocyte adherence back to control levels. Conclusions-NO exerts a tonic antiadherent effect in the cerebral microcirculation by inactivation of adherence-promoting superoxide radical formation. Cer ebral ischemia is associated with an inhibition of NOS or lower levels of NO, which results in leukocyte-endothelial adherence that can be p revented by NO donors. The latter may be useful therapeutically to pre vent the purported vascular and parenchymal dysfunction and injury cau sed by activated leukocytes in ischemic brain.