ENDOTHELIN AND OXIDANT STRESS IN CEREBRAL VASOSPASM

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Cerebral vasospasm is delayed onset of vasoconstriction occurring days after aneurysmal subarachnoid hemorrhage. It is a major cause of stroke and death after subarachnoid hemorrhage. Hemoglobin and oxidant stress induced by it may be important in the pathogenesis of vasospasm. We found that heme oxygenase-1 messenger ribonucleic acid (mRNA) and protein are increased in smooth muscle cells exposed to hemoglobin. Heme oxygenase-1 protein is also increased in vasospastic arteries. Heme oxygenase-1 expression is known to be induced by oxidative stress and by heme in other types of cells, where it may protect against these cytotoxic stimuli. The long-term objective of this work is to determine the role of heme oxygenase-1 in vasospasm. The specific aims are: (1) To define the time course and dose-dependence of induction of heme oxygenase-1 and ferritin mRNA and protein in response to hemolysate and purified hemoglobin in cultured cerebrovascular smooth muscle cells. Hypothesis: Heme oxygenase-1 and ferritin are induced by solutions that contain heme, such as hemolysate and purified hemoglobin. (2) To define the time course of induction of heme oxygenase- 1 and ferritin mRNA and protein in the rat basilar artery after subarachnoid hemorrhage. Hypothesis: Vasospasm is associated with hemolysis, exposure of smooth muscle cells to heme, and induction of heme oxygenase-1 and ferritin. The induction of heme oxygenase-1 and ferritin is associated with the resolution of vasospasm. (3) To determine the effects of induction of heme oxygenase-1 and ferritin on vasospasm. Hypothesis: Induction of heme oxygenase-1 and ferritin decrease vasospasm.