The regulation of blood flow to the brain is of great importance. Of interest, cerebral arteries of the fetus and newborn demonstrate major differences in response to norepinephrine (NE) and other contractile amines as compared with adult (increased sensitivity, decreased efficacy, et cetera). Thus, an understanding of the basic adrenergic signal transduction mechanisms of the cerebral vessels, how these change with development, and in response to various physiologic and pathophysiologic stimuli is critical. The overall hypothesis of the studies is that the alteration of cerebrovascular reactivity during development is secondary to changes in the basic biochemical signal transduction mechanisms. In cerebral arteries of the fetus, newborn; and adult we will test five specific hypotheses as follows. 1) Vessel specific and developmental changes in NE-induced cerebrovascular responses result from changes in the interactions and negative feedback of protein kinase C and cAMP/protein kinase A on inositol-1,4,5- trisphophate (Ins(1,4,5)P3) response. 2) Differences in NE-induced contractility are, in part, secondary to differences in the density and/or affinity of the Ins(1,4,5)P3-receptor. 3) Altered responses are secondary to differences in Ins(1,4,5)P3-induced Ca2+ release and the resultant intracellular CA2+ concentrations. 4) Differences in (NE)- induced cerebrovascular responses result from differences in the role of plasma membrane Ca2+ channel (or K+ channels) in the several vessels and age groups. 5) Differences in responses result from differences in Ca2+ release from sarcoplasmic reticulum Ca2+ pools. To address the effects of maturation, studies will be performed in term fetal and newborn lambs, and nonpregnant sheep. To examine the role of differences in arterial size and type, experiments will be performed in common carotid and middle cerebral arteries (both first and second order branches). These studies will provide new and important insights into the basic mechanisms of the regulation of cerebral vascular reactivity in adult, as well as during the course of development. They will also contribute to understanding the pathophysiology of clinical problems associated with the dysregulation of cerebral blood flow, intracerebral hemorrhage, various neurological sequelae (such as cerebral palsy, seizure disorders, mental retardation, and minimal brain dysfunction, et cetera).
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