Controlled release of a nitric oxide donor for the prevention of delayed cerebral vasospasm following experimental subarachnoid hemorrhage in nonhuman primates

Object. Results of prior Studies in rats and rabbits show that the alteration of vasomotor tone in vasospasm following periadventitial blood exposure may be reversed, at least in part, by the administration of compounds releasing nitric oxide (NO). The authors have now generalized this finding to nonhuman primates. Methods. Ten cynomolgus monkeys underwent cerebral angiography before and 7 days following the induction of subarachnoid hemorrhage (SAH) by the placement of 2 to 3 ml clotted autologous blood around the supraclinoid carotid, proximal anterior cerebral, and proximal middle cerebral arteries. An ethylene vinyl acetate copolymer, either blank (five animals) or containing 20% w/w (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate(DETA/NO, 4.3 mg/kg; five animals) was placed adjacent to the vessels at the time of surgery. Animals were killed on Day 7 post-SAH following repeated cerebral angiography. The mean percentage of control vascular areal fraction was calculated from angiograms. Cerebral vessels were sectioned and the mean percentage of lumen patency was calculated. One animal that had received the DETA/NO polymer died prior to repeated angiography. In the remaining animals, DETA/NO caused a significant decrease in vasospasm compared with controls, according to both angiographic (84.8 +/- 8.6 compared with 56.6 +/- 5.2%, respectively, p < 0.05) and histological studies (internal carotid artery 99.3 +/- 1.8 compared with 60.1 +/- 4.4%, respectively, p < 0.001; middle cerebral artery 98.4 +/- 3 compared with 56.1 +/- 3.7%, respectively, p < 0.001; and anterior cerebral artery 89.2 +/- 8.5 compared with 55.8 +/- 6.3%, respectively, p < 0.05). Conclusions. The controlled release of DETA/NO is effective in preventing delayed cerebral vasospasm in an SAH model in nonhuman primates. The death of one animal in the treatment group indicates that the present dosage is at the threshold between therapeutic efficacy and toxicity.