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). CONCLUSION: 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.