application) Recent evidence suggests that several types of potassium (K+) channels are present in cerebral blood vessels, and that activation of these channels may play a critical role in relaxation. One major goal of this proposal is to examine the role of K+ channels in regulation of cerebral circulation. Studies are proposed to test the hypothesis that Ca++-dependent K+ channels modulate cerebral vasoconstrictor responses to increases in mean arterial pressure and pulse pressure in vivo. The second major goal is to examine the role of K+ channels in mediation of cerebral vasodilator responses to reactive oxygen species. Studies are proposed to examine the hypotheses that K+ channels mediate cerebral vascular responses to reactive oxygen species (especially H2O2), and that bradykinin, arachidonic acid, and acute severe hypertension, which produce vasodilatation of cerebral vessels. The third major goal of these studies is to examine the role of extracellular superoxide dismutase (ECSOD) in cerebral blood vessels. Recent evidence suggests that ECSOD accounts for about half of total SOD activity in blood vessels. The role of ECSOD is poorly defined, in part because a source for obtaining ECSOD is not available. The gene for ECSOD has been cloned into an adenoviral vector, and thus a method is available to produce ECSOD. Novel methods will be used to transfer genes to blood vessels, with perivascular application to intracranial vessels and the carotid artery in vivo. Studies are proposed to measure ECSOD activity in cerebral vessels, and to use adenovirus-mediated gene transfer of ECSOD to the carotid artery and to intracranial vessels. Studies are planned to test the hypothesis that gene transfer of ECSOD to the carotid artery in vitro and in vivo increases activity of ECSOD and preserves endothelial function after oxidative stress. Studies are also proposed to test the hypothesis that, after gene transfer to intracranial vessels, increases in ECSOD activity prevent """"""""breakthrough"""""""" in autoregulation of cerebral blood vessels and protect the blood-brain barrier against disruption during acute severe hypertension.
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