The overall objective of this proposal is to define the mechanisms of regulation of cerebral blood flow (CBF) and metabolism under a variety of unusual circumstances. A major aim will be to integrate the activities of various disciplines such that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. Several factors (nervous system, chemical, metabolic, pharmacologic, and mechanical) exert control over the cerebral vasculature under a variety of physiologic and pathophysiologic conditions. The projects outlined in this proposal attempt to clarify some of the mechanisms by which these regulatory factors work in a variety of conditions. In Project 1, the potential role of nitric oxide in the regulation of CBF and metabolism and its role in mediating vascular changes or neurologic injury in ischemia/reperfusion in the setting of global and focal ischemia will be examined. Project 2 investigates one of the mechanisms whereby acidosis contributes to ischemic injury by utilizing 31P magnetic resonance spectroscopy to measure changes in pHi and ATP during and following incomplete cerebral ischemia. These studies will also be performed in diabetic animals, so the impact of the acidosis mechanism may be relevant to diabetic patients with stroke. Project 3 examines mechanisms of how interventions made during cardiopulmonary resuscitation (CPR) affect cerebral perfusion, metabolism and function during and following CPR. These studies will deal with the effect of CPR on brain pH in adult animals and the contribution of excitotoxic mechanisms of injury in the pediatric CPR model. In Project 4, developmental mechanisms of cerebrovascular regulation will be examined in utero, and we will establish a novel model of perinatal cerebral injury that could occur during labor when homeostatic defense mechanisms fail. The consequences of fetal head compression may have an important bearing on premature and term human newborns predisposed to neurological injury by other prenatal factors, and thereby contribute to cerebral palsy and other neurologic disabilities. Finally, Project 5 will determine whether neurohypophyseal (NH) blood vessels actively participate in neurosecretory events or merely serve as conduits for hormone passage. These studies will provide information about the role NH blood vessels play in neuroendocrine function and about their regulation. The multidisciplinary approach of the investigators and their different expertise permits novel and innovative approaches to questions concerning the regulation of CBF in health and disease.
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