Cortical spreading depression (CSD) is a wave of depolarization that results in complex changes in pial arteriolar diameter, intense vasodilation lasting approximately 2 minutes, a return of diameter to baseline for several minutes, and then a prolonged period of vasoconstriction and reduced responsiveness to dilator and constrictor stimuli. CSD can be initiated by microapplication to the brain of K+ or excitatory amino acid neurotransmitters, electrical stimulation, trauma such as physical puncture of the brain or applied pressure, or by anoxia/asphyxia. Our preliminary observations in adult rabbits have led to the development of three hypotheses related to cerebral hemodynamic effects of CSD: a) CSD dilates pial arterioles via mechanisms intrinsic to the vessel wall--activation of perivascular fibers associated with the trigeminal nerve, or by an endothelium-dependent pial arteriolar dilation arising secondary to dilation of intracortical arterioles; b) prostaglandin endoperoxide synthase products (prostanoids and/or free radicals) limit arteriolar dilation during CSD; and c) delayed post-CSD vasoconstriction and reduced responsiveness are due to presence of prostaglandin endoperoxide synthase products. To test these hypotheses, two specific aims will be addressed in anesthetized rabbits. 1) DETERMINATION OF THE MECHANISM(S) OF CEREBROVASCULAR DILATION DURING CSD; AND 2) DETERMINATION OF THE MECHANISM(S) OF CEREBROVASCULAR CONSTRICTION AND REDUCED RESPONSIVENESS FOLLOWING CSD. We will use several complimentary methods, including: the """"""""closed"""""""" cranial window to allow virtually continuous measurement of pial arteriolar diameter and periodic sampling of perivascular cerebrospinal fluid for subsequent prostanoid determination using radioimmunoassay; cerebral blood flow determination using radioactive microspheres; and superoxide anion detection using an assay involving superoxide dismutase inhibitable nitroblue tetrazolium reduction. These studies will expand our understanding of vascular control mechanisms in the brain and may provide information to allow development of therapeutic approaches to alleviate immediate and delayed vascular and neuronal impairments associated with CSD-Iike events.
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