Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer

OBJECTIVE: Despite improvements in the care of patients with aneurysmal sub arachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of m orbidity and death. There is now evidence that a decrease in the local avai lability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. W e evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-( 2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) fo r the treatment of chronic posthemorrhagic vasospasm in the rat femoral art ery model. METHODS: The release kinetics of ethylene/vinyl acetate copolymers loaded w ith 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induc ed in the left femoral artery of adult male Fischer 344 rats (n = 35) by ex posure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral arte ry. On the 8th day after blood exposure (at the peak of vasospasm in this m odel), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing an d morphometric analyses. Vasospasm was expressed as the percent lumen paten cy of the treated left artery, compared with the control right artery. RESLTS: The in vitro release kinetics demonstrated that the 20% DETA/NO-loa ded polymers released up to 15% of their total drug load during a 9-day per iod. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 +/- 7.2% versus 67.6 +/- 5.8%, 104.6 +/- 5.5% versus 64.9 +/- 1.7%, and 102 .4 +/- 5.1% versus 73.6 +/- 1.4%, respectively; mean standard error of the mean percent lumen patency; P < 0.001). No adverse effects of treatment wer e observed. CONCLUSION: The diazeniumdiolate NO donor DETA/NO can be effectively releas ed from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhag ic vasospasm in the rat femoral artery and can reverse established vasospas m. No adverse effects of DETA/NO were observed in this model.