Fetal sheep respond to hypotension with reflex hormonal and hemodynamic responses which return blood pressure to normal levels. We have demonstrated that the reflex vasomotor and heart rate responses and the reflex hormonal responses are mediated by both baroreceptor- and chemoreceptor- reflexes. However, a significant portion of the reflex hormonal and hemodynamic responses to hypotension are not mediated by either peripheral baroreceptors or chemoreceptors. We have hypothesized that hypotension reduces fetal cerebral blood flow and that the reduced blood flow is transduced within the brain to stimulate hormonal and hemodynamic responses. Specifically, we have hypothesized that reductions in cerebral blood flow stimulate the local production of prostanoids within the central nervous system which, in turn, stimulate adrenocorticotropin (ACTH) and cardiovascular responses. The proposed experiments will focus on two prostanoids, prostaglandin E2 (PGE2) and thromboxane A2 (TxA2), which we know to potently alter blood pressure, heart rate, and ACTH secretion by an action at the brain. In support of this hypothesis, we have demonstrated that: 1) a significant proportion of the reflex hormonal and hemodynamic responses to hypotension in the fetus is not dependent upon arterial or cardiopulmonary baroreceptors or chemoreceptors; 2) both PGE2 and TxA2 act at the brain to alter cardiovascular and endocrine function in both the fetus and the adult animal; and 3) prostanoids can be made within the brain. Results of experiments from other laboratories demonstrate that both PGE2 and TxA2 are produced within the central nervous system in response to a reduction in cerebral blood flow. In all experiments, we will use chronically catheterized and instrumented fetal sheep and will measure ACTH and cardiovascular (blood pressure, heart rate, and distribution of combined ventricular output). There are four studies proposed. In the first study, we will measure responses to reduced cerebral perfusion pressure. From data existing in the literature, we expect that reductions in cerebral perfusion pressure will reduce cerebral blood flow and will stimulate local (prostanoid generation) and reflex (hormonal and hemodynamic) responses. In the second study, we will measure hormonal and hemodynamic responses to administration of U46619, a TxA2 mimetic, or PGE2, into the cerebral ventricles to test the specific effects of these prostanoids on ACTH and cardiovascular responses. In the third study, we will test the role of endogenously generated TxA2 and PGE2 on the reflex responses to reduced fetal cerebral blood flow. In the fourth study, we will use immunocytochemistry to determine the localization of the prostanoid synthetic enzymes, PGHS1, PGHS2 and thromboxane synthetase, in the regions of the brain, hypothalamus and brainstem, responsible for control of ACTH and cardiovascular function. We will also use Western blots to determine if the levels of these enzymes are altered with hypoperfusion. We believe that, because of the potent effects of these prostanoids on the fetal brain, the proposed experiments will identify an important mechanism for the maintenance of blood pressure in the fetus. Ultimately, understanding the mechanisms important for the control of fetal blood pressure is important for the clinical management of women in late gestation and their fetuses. Clinical management of late-gestation fetal human patients has included, recently, fetal surgery for correction of congenital anomalies. Surgery without knowledge of mechanisrns governing blood pressure control is likely to be less succesful. Improvement of our knowledge of the rnle of prostanoids in the control of fetal blood pressure is also quite important in light of the use of prostaglandin synthase inhibitors clinically for various reasons, including tocolysis.
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