Abstract
1. Approximately one-third of the morbidity and mortality due to aneurysmal subarachnoid hemorrhage (SAH) is caused by delayed ischemic neurological deficit (DIND) due to cerebral vasospasm. 2. Compared to prolonged arterial constriction in other parts of the body, cerebral vasospasm is characterized by its long duration and refractoriness to vasodilators such as calcium antagonists. 3. Whereas oxyhemoglobin (oxyHb) liberated into the CSF from the subarachnoid clot has been deemed the causative agent of vasoconstriction, the biochemical mechanisms whereby oxyHb elicits prolonged constriction of the cerebral arteries has remained elusive. Here, we suggest that oxyHb triggers the generation of reactive oxygen intermediates (ROI) within the CSF. 4. Multiple lines of evidence indicate that the occurrence of vasospasm, namely, prolonged smooth muscle contraction, is due to the following intracellular events. 5. First, hydroxyl radicals (OH*), the most reactive species of ROI, are generated within the cerebral arterial wall via the Fenton and Haber-Weiss reactions catalyzed by oxyHb. Second, subsequent peroxidative membrane damage in the arterial smooth muscle cell enhances the metabolism of phosphatidylcholine and phosphatidylethanolamine, leading to a rise in the intracellular level of diacylglycerol, an endogenous activator of protein kinase C. 6. The prolonged arterial contraction that occurs during vasospasm is attributable primarily to the activation of protein kinase C, not to the Ca2+/calmodulin system. In this article, literature relevant to the above thesis is reviewed, and the rationale for the antioxidant therapy against cerebral vasospasm is discussed.