ENDOTHELIUM DEPENDENT CONTRACTIONS &CEREBRAL VASOSPASM

The causation of chronic spasm of the cerebral arteries following subarachnoid hemorrhage is unknown. Exposure of the external surfaces of cerebral arteries to blood products leads to the excessive production of prostanoids associated with the generation of oxygen-derived free radicals. The proposition to be tested is that oxygen-derived free radicals particularly superoxide anions, released from endothelial cells, mediate endothelium-dependent contractions by inactivation of endothelium-derived relaxing factor(s), and contraction of smooth muscle either by direct action or by production of prostanoids. The role of cyclooxygenase in basal and stimulated production in endothelial cells of superoxide anions will be determined, as will the effects of exogenously generated superoxide anions on endothelial and smooth muscle cells. Experiments will be conducted on isolated canine basilar arteries that had been subjected to autologous venous blood injected into the cisterna magna. Endothelium- dependent contractions will be analyzed in the presence of superoxide dismutase, catalase and deferoxamine to examine the role of superoxide anions, hydrogen peroxide and hydroxyl radicals. Selective receptor antagonist and enzymatic pathway inhibitors will be used and the production of prostanoids will be measured to examine the role of endoperoxides, prostaglandins and thromboxane A2 in mediating endothelium-dependent contractions. If superoxide anions or other free radicals cause contractions, the effects of various substance (oxygen-derived free radical scavengers and anti-inflammatory drugs) will be examined, to determine whether they can reduce or prevent endothelium-dependent contraction and chronic cerebral vasospasm. It is anticipated that those studies will enhance knowledge of the mechanisms and mediators of cerebral vasospasm and provide indications for therapies.