Baroreceptor and chemoreceptor reflexes are actively involved in the control of fetal blood pressure and in the maintenance of blood flow to the placenta and to the metabolizing tissues. The present project is an investigation into the mechanism of the baro- and chemoreflexes. In the first two funding periods of this project, we discovered and explored the interaction between changes in fetal blood pressure and prostaglandin generation in the fetal brain. In the immediate past funding period, we found that prostaglandin synthase -1 (PGHS-1) activity in the fetal brain augments reflex activity and that PGHS-2 activity decreases reflex activity. We found that denervation of the arterial baroreceptor/chemoreceptors does not, by itself, alter the expression of these enzymes in the fetal brain;PGHS-2 expression (and likely subsequent activity) is upregulated by transient hypotension. We have also initiated the use of a cell culture model to make significant progress in understanding the molecular mechanism of the PGHS-2 response to oxygen and glucose deprivation. These discoveries suggest that the immediate response to hypotension in the fetus is dependent upon PGHS-1 acitivty, but that the more delayed increase in PGHS-2 may bias subsequent responses and predispose the fetus to hypoxic damage. These findings have led us to propose the following specific aims, to propose to answer the following questions: 1) is there an association of glutaminergic pathways and prostanoids in the mediation of the reflex respones to cerebral hypoperfusion? 2) Is the ability of the fetus to maintain blood pressure and blood gases during hypovolemia impaired by blockade of prostaglandin biosynthesis or NMDA receptors? 3) What is the molecular and cellular basis of the upregulation of PGHS-2 in response to hypotension? In the proposed 5-year continuation of this project, the answers to these questions will significantly enhance our understanding of the mechanism by which prostanoids act within the brain to alter cardiovascular function. We will answer all of these questions using in vivo as well as cellular and molecular techniques. The results will build on our previous discoveries to significantly improve our understanding of the mechanism of the fetal stress response during hypotension. The results will identify the processes within the reflex pathway that can be manipulated pharmacologically and therefore enhance fetal survival during hypotensive stress.
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