Ja. French et al., MECHANISMS OF STROKE IN SICKLE-CELL DISEASE - SICKLE ERYTHROCYTES DECREASE CEREBRAL BLOOD-FLOW IN RATS AFTER NITRIC-OXIDE SYNTHASE INHIBITION, Blood, 89(12), 1997, pp. 4591-4599
The etiology of stroke in sickle cell disease is unclear, but may invo
lve abnormal red blood cell (RBC) adhesion to the vascular endothelium
and altered vasomotor tone regulation. Therefore, we examined both th
e 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 m
icrocirculation 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 con
trol AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused i
nto rats prepared with LDF probes after pretreatment (40 mg/kg intrave
nously) with the NO synthase inhibitor, N-omega-nitro-L-arginine methy
l ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated wit
h systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrea
se in LDF and died within 30 minutes after the RBC infusion (P = .0012
). In contrast, all control groups completed the experiment with stabl
e LDF and hemodynamics, Four rats received a localized superfusion of
L-NAME (1 mmol/L) through the cranial window followed by infusion of S
S-RBCs, Total cessation of flow in all observed cerebral microvessels
occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs, W
e conclude that the NO pathway is critical in maintaining cerebral blo
od 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 ei ther directly, by disrupting blood flow
, or indirectly, by disturbing the vascular endothelium. (C) 1997 by T
he American Society of Hematology.