MECHANISM OF CEREBRAL VASODILATION DUE TO ISOFLURANE

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The purpose of this proposal is to determine the mechanism by which volatile anesthetics affect cerebrovascular control. We will test the hypothesis that volatile anesthetics causes cerebral vasodilation by interfering with cerebral vasoconstriction mediated by an alpha2-adrenoreceptor linked by G protein to cyclic AMP. In project 1, we will test the hypothesis that alpha2 receptors located in or adjacent to the cerebrospinal fluid space affect global cerebral blood flow during volatile anesthesia. We will compare injection at different intrathecal locations with intravenous injection of an alpha2 agonist, compare distribution of a radiolabelled alpha2 agonist with regional cerebrovascular changes, and assess cerebrovascular effects of a specific alpha2 antagonist during volatile anesthesia. In project 2, we will test the hypothesis that alpha2 receptor action requires a G protein for transduction to a cAMP effector. We will assess blockade of G protein function (pertussis toxin pretreatment) and direct manipulation of cAMP levels (forskolin ) on cerebral blood flow during volatile anesthesia and on the effect of an alpha2 agonist administered during volatile anesthesia. In project 3, we will test the hypothesis that alpha2 receptor stimulation during volatile anesthesia affects cerebrovascular responsivity. We will assess cerebrovascular responsivity to perfusion pressure and blood gas changes before and after administration of a highly specific alpha2 agonist during volatile anesthesia. In project 4, we will test the hypothesis that pial arterioles respond directly to an alpha2 agonist, alpha2 antagonist, forskolin and pertussis toxin, and thereby differentiate central neurogenic alpha2 mechanisms versus direct vascular alpha2 adrenergic mechanisms. This proposal will improve understanding of the mechanism of cerebrovascular control during volatile anesthesia and will allow prediction of interactions with drugs and diseases which alter alpha2-- adrenoreceptor or G protein function.