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Mechanisms of stroke in sickle cell disease: sickle erythrocytes decrease
cerebral blood flow in rats after nitric oxide synthase inhibition
JA French , D Kenny, JP Scott, RG Hoffmann, JD Wood, AG Hudetz and CA Hillery
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA.
The etiology of stroke in sickle cell disease is unclear, but may involve
abnormal red blood cell (RBC) adhesion to the vascular endothelium and
altered vasomotor tone regulation. Therefore, we examined both the adhesion
of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on
cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The
effect of SS-RBCs was studied in the rat cerebral microcirculation using
either a cranial window for direct visualization of infused RBCs or laser
Doppler flowmetry (LDF) to measure RBC flow. When fluorescently labeled
human RBCs were infused into rats, SS-RBCs had increased adhesion to rat
cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed
SS-RBCs or AA- RBCs were infused into rats prepared with LDF probes after
pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor,
N-omega-nitro- L-arginine methyl ester (L-NAME), or the control isomer,
D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9
experienced a significant decrease in LDF and died within 30 minutes after
the RBC infusion (P = .0012). In contrast, all control groups completed the
experiment with stable LDF and hemodynamics. Four rats received a localized
superfusion of L-NAME (1 mmol/L) through the cranial window followed by
infusion of SS-RBCs. Total cessation of flow in all observed cerebral
microvessels occurred in 3 of 4 rats within 15 minutes after infusion of
SS-RBCs. We conclude that the NO pathway is critical in maintaining
cerebral blood flow in the presence of SS-RBCs in this rat model. In
addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may
contribute to cerebral vaso-occlusion either directly, by disrupting blood
flow, or indirectly, by disturbing the vascular endothelium.
Volume 89,
Issue 12,
pp. 4591-4599,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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