application) The overall hypothesis to be tested is that oxytocin is an important contributor to neonatal cerebrovascular control. This hypothesis is supported by many interconnected findings from piglets: 1) vasoactive levels of oxytocin are found in blood and cerebrospinal fluid, 2) oxytocin is contained in perivascular nerves in the adventitia of cerebral resistance vessels, 3) oxytocin responses in the cerebral circulation are different from those of vasopressin, 4) the normal cerebral arteriolar response to oxytocin or a specific oxytocin agonist is dilation, 5) dilator responses to oxytocin are mediated by endothelial derived prostaglandins and nitric oxide, 6) brief hypoxia attenuates dilator responses to oxytocin, 7) ischemic stress reverses oxytocin effects to potent constriction in spite of increased levels of endothelial cyclooxygenase and nitric oxide synthase, 8) ischemic stress depletes perivascular nerves of oxytocin and 9) ischemic stress results in dramatic increases in superoxide anion. Based upon these findings and those in the literature, the investigators propose the following specific hypotheses: 1) dilator effects of oxytocin are suppressed following ischemic stress due to lack of substrate for nitric oxide and prostaglandins and/or hypoxia induced suppression of NOS, 2) constrictor effects of oxytocin are due to direct activation of vascular smooth muscle and are resistant to or potentiated by ischemic stress, and 3) perivascular innervation is an important source of oxytocin to cerebral blood vessels. To test these hypotheses, two specific aims will be addressed using newborn pigs: 1) elucidation of mechanisms involved in reversal of oxytocin induced cerebrovascular dilation following ischemic stress and 2) characterization of oxytocinergic innervation of cerebral blood vessels. The investigators will use the closed cranial window and intravital microscopy to characterize responses of individual arteries and arterioles in vivo. In addition, they will use immnocytochemistry to determine the presence and distribution of oxytocin innervation of brain blood vessels. This investigation will explore control mechanisms in neonatal animals during normal and pathological conditions. It is anticipated that the findings will be of clinical relevance and lead to therapies that improve outcome in stressed babies.
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