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Adenosine triphosphate and hemoglobin in vasospastic monkeys

R. Loch Macdonald, Bryce Weir, John Zhang, Linda S. Marton, Michael Sajdak, and Lydia M. Johns

Adenosine triphosphate (ATP) is a vasoactive compound found in high levels inside erythrocytes that may contribute to vasospasm occurring after subarachnoid hemorrhage (SAH). This study was instituted to test whether ATP causes vasospasm in a monkey model.

Thirty-two monkeys were randomized to four groups of eight monkeys each to undergo cerebral angiography at baseline (Day 0) and then at Day 7 after subarachnoid placement of: 1) agarose, 2) ATP in agarose, 3) autologous hemolysate in agarose, or 4) purified human hemoglobin A0 in agarose. Vasospasm was assessed by comparison of Day 0 and Day 7 angiograms between and within groups and by pathological examination of a subset of perfusion-fixed monkeys. Levels of adenine nucleotides were measured on Day 7 in subarachnoid agarose by high-pressure liquid chromatography.

There was significant vasospasm of the right middle cerebral artery in groups given ATP (-28 ± 7% reduction, paired t-test, p < 0.05), hemolysate (-23 ± 7%, p < 0.05), or pure hemoglobin (-15 ± 2%, p < 0.005). Analysis of variance revealed no significant differences between groups in diameters of cerebral arteries on Day 7. Pathological examination showed mild inflammation in the subarachnoid spaces of animals exposed to hemolysate or hemoglobin and less inflammation in those given ATP or agarose. There were no pathological changes in the cerebral arteries of animals in any group. Most of the ATP diffused out of the subarachnoid agarose by Day 7, and levels of adenine nucleotides in subarachnoid agarose were higher on Day 7 in animals exposed to hemoglobin or hemolysate.

It is concluded that ATP could contribute to vasospasm occurring after SAH but that further investigations are necessary to determine if levels of ATP adjacent to vasospastic arteries are sufficient to contribute to vasospasm. In addition, no observation was made of severe vasospasm with histopathological changes in the arteries equivalent to that produced by whole blood clot in the subarachnoid space of monkeys. It should be determined whether this is because a single compound, such as ATP or hemoglobin, causes vasospasm, but that placing the compound in agarose alters its delivery and decreases the amount of vasospasm produced, or whether vasospasm is a more complex, multifactorial process.