Traumatic brain injury (TBI) results in hyperemia followed by hypoperfusion and reduced vascular responsiveness. Our preliminary evidence indicates that TBI causes cerebral hypoperfusion and impairs cerebral vasodilatory responses to hypotension. In humans, hemorrhagic hypotension after TBI increases mortality. We have developed four hypotheses to explain these events: 1. Cerebral hypoperfusion after TBI is due to release of vasoactive substances (endogenous opioids or vasoconstrictor prostanoids), the relative importance of which depend on the severity of TBI. 2. Reduced cerebral vascular responsiveness is due to increased production of free oxygen radicals, especially at higher levels of TBI. 3. Traumatic vascular injury occurs primarily at the level of the vascular endothelium. 4. Due to this loss of compensatory cerebral vasodilatory responses, hemorrhagic hypotension after TBI produces more severe neuronal injury than the same degree of hypotension alone.
The Specific Aims of this project are to: I. characterize the temporal course of cerebral hypoperfusion after TBI and to determine the relative contribution of opiate and eicosanoid mechanisms at different injury levels. II. investigate the role of free oxygen radicals to reduced vascular responsiveness after trauma. III. determine whether endothelium-dependent vasodilatory mechanisms are impaired by superoxide or hydroxyl radicals generated by TBI. IV. investigate the histopathological consequences of arterial hypotension after TBI. Cerebral blood flow (CBF)(microspheres) will be measured after TBI in rats treated with kappa opiate antagonists or cyclooxygenase inhibitors (Aim 1). In rats after TBI, the production of free radicals, the effects of treatment with an antioxidant enzyme (SOD) on the responsiveness of pial arterioles to dilator stimuli (hypotension, topical acetylcholine) and the relationship between CBF (iodoantipyrine) and metabolism (2-deoxyglucose) after treatment with SOD will be measured (Aim II). The role of the vascular endothelium in cerebral vasodilatory responses to hypotension and hypoxia after TBI will be determined (Aim III). Histopathological effects of arterial hypotension Will be compared in rats after TBI or sham injury (Aim IV).
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