Controlled delivery of nitric oxide inhibits leukocyte migration and prevents vasospasm in haptoglobin 2-2 mice after subarachnoid hemorrhage.
OBJECTIVE
Cerebral vasospasm is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH) occurs. The haptoglobin 2-2 genotype likely increases the risk for developing posthemorrhagic vasospasm, but potential treatments for vasospasm have never been tested in an animal model of this genotype. We used the nitric oxide (NO) donor diethylenetriamine (DETA)/NO incorporated into ethylene/vinyl acetate (EVAc) polymers to evaluate the efficacy of controlled NO repletion in a haptoglobin 2-2 mouse basilar artery SAH model.


METHODS
Mice were randomized to 3 groups: autologous blood injection and empty polymer implantation into the subarachnoid space (n = 16); blood injection and 30% DETA/NO-EVAc implantation (n = 20); and sham operation (n = 19). At 24 hours after surgery, activity level was assessed on a 3-point scale, and basilar arteries were processed for morphometric measurements. Leukocyte extravasation was assessed by immunohistochemistry (n = 12).


RESULTS
Treatment with controlled release of NO from DETA/NO-EVAc polymers after SAH resulted in a significant increase in basilar artery lumen patency (73.3% +/- 4.3% versus 96.5% +/- 4.3%, mean +/- standard error of the mean; P = 0.01), a significant improvement in activity after experimental SAH (2.14 +/- 0.14 versus 2.56 +/- 0.10 points; P = 0.025), and a significant decrease in extravasated leukocytes (21 +/- 4.55 versus 6.75 +/- 3.77 leukocytes per high-power field, untreated versus treated mice; P = 0.001).


CONCLUSIONS
Treatment with controlled release of NO prevented posthemorrhagic vasospasm in haptoglobin 2-2 mice, and mitigated neurological deficits, suggesting that DETA/NO-EVAc would be an effective therapy in patients with a genotype that confers higher risk for vasospasm after SAH. In addition to smooth muscle relaxation, inhibition of leukocyte migration may contribute to the therapeutic mechanism of NO.
Momin
Eric N
EN
Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Schwab
Kristin E
KE
Chaichana
Kaisorn L
KL
Miller-Lotan
Rachel
R
Levy
Andrew P
AP
Tamargo
Rafael J
RJ
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004337:Drug Carriers; D045462:Endothelium-Dependent Relaxing Factors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000008:administration & dosage*; D011145:Polyvinyls; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D014654:Vascular Patency / Q000187:drug effects; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000517:prevention & control*
D004337:Drug Carriers; D045462:Endothelium-Dependent Relaxing Factors; D006242:Haptoglobins; D011145:Polyvinyls; C016438:ethylenevinylacetate copolymer; D009569:Nitric Oxide