Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide

Abstract

Background and Purpose-Recent studies indicate that leukocytes are important contributors to secondary vascular and parenchymal injury after cerebral ischemia. The present study was undertaken to define nitric oxide (NO)Ϫbased mechanisms that regulate leukocyte-endothelial interactions in the cerebral vasculature, how these mechanisms are affected by cerebral ischemia, and whether NO-based therapies can affect postischemic leukocyte dynamics. Methods-Leukocyte adherence to pial venules of anesthetized newborn piglets was quantified by in situ fluorescence videomicroscopy through closed cranial windows during basal conditions and during reperfusion after 9 minutes of asphyxia. Nitric oxide synthase (NOS) was inhibited by local window superfusion of L-nitroarginine; superfusion of sodium nitroprusside was used to donate NO. Results-Local inhibition of NOS under resting conditions increased leukocyte-endothelial adherence 2.2-fold and 3.9-fold over baseline values after 1 hour and 2 hours, respectively; this response was completely blocked by cosuperfusion with L-arginine. Cosuperfusion of superoxide dismutase reversed L-nitroarginineϪinduced leukocyte adherence by 89% and 63% at these respective time points. The extent of acute leukocyte adherence elicited by NOS inhibition was similar in magnitude to that observed during the initial 2 hours of reperfusion after asphyxia. Leukocyte adherence was not additionally increased in asphyxic animals treated with L-nitroarginine. Sodium nitroprusside robustly inhibited asphyxia-induced leukocyte adherence back to control levels. Conclusions-NO exerts a tonic antiadherent effect in the cerebral microcirculation by inactivation of adherencepromoting superoxide radical formation. Cerebral ischemia is associated with an inhibition of NOS or lower levels of NO, which results in leukocyte-endothelial adherence that can be prevented by NO donors. The latter may be useful therapeutically to prevent the purported vascular and parenchymal dysfunction and injury caused by activated leukocytes in ischemic brain.

Albumin Therapy of Transient Focal Cerebral Ischemia

“…By contrast, nitric oxide synthase inhibition augments and prolongs postischemic leukocyte adhesion by mechanisms thought to involve principally a decrease in velocity or shear rate, 46 although others have suggested that nitric oxide exerts a chronic antiadherent effect in the cerebral microcirculation by inactivating adhesionpromoting superoxide radical formation. 47 The latter observation is pertinent here in that serum albumin, via its free sulfhydryl group, reacts with oxides of nitrogen to form a stable S-nitrosothiol with properties resembling endotheliumderived relaxing factor. 48 By this means, albumin may both affect vascular tone and exert antiplatelet effects within the microcirculation.…”

Combined Endothelial Nitric Oxide Synthase Upregulation and Caveolin-1 Downregulation Decrease Leukocyte Adhesion in Pial Venules of Ovariectomized Female Rats

“…Monitoring only resting leukocyte behavior, Gidday et al 16 reported an increase in pial venular leukocyte adhesion in newborn pigs in the presence of acute NOS inhibition. In contrast, other investigators have reported no changes in basal leukocyte adhesion in rat pial venules after NOS inhibitor administration, 13,17 although in 1 of those studies 13 the proadhesive actions of leukotriene B 4 were enhanced in the presence of NOS inhibition.…”

“…Previous studies on the brain vasculature 13,16,17 involved acute NOS blockade paradigms, whereas ovariectomy is essentially a model of chronic eNOS repression. In the peripheral circulation, chronic inhibition of basal release of NO induces adhesion molecule expression, 18 indicative of a tonic anti-inflammatory role of NO.…”

Timing of Neutrophil Depletion Influences Long-Term Neuroprotection in Neonatal Rat Hypoxic-Ischemic Brain Injury

“…Superoxide produced by neutrophils and endothelial cells during reperfusion promotes adherence, but it is inactivated by binding to nitric oxide (37). During cerebral ischemia there is an inhibition of nitric oxide production which enhances neutrophil-endothelial adherence (38).…”