In this renewal application, Dr. Pearce proposes a series of studies that focus on the mechanisms potentially responsible for the observed age-related differences in late fetal/neonatal and adult cerebral artery reactivity to contractile amines. Based on the general hypothesis that maturation modulates cerebrovascular reactivity by enhancing IP3-dependent, and depressing IP3-independent mechanisms of pharmacomechanical coupling, Dr. Pearce proposes three multifaceted specific aims.
These specific aims i nclude: 1) to determine if agonist-stimulation produces less intracellular calcium release and greater entry of extracellular calcium in cerebral vessels from immature vs. mature sheep, 2) to determine if attenuated IP3 receptor GAIN is the main factor responsible for depressed cerebrovascular reactivity to IP3 observed in neonatal sheep, and 3) to determine if IP3-independent agonist-induced shifts in myofilament Ca2+ sensitivity are greater in cerebral arteries from immature vs. mature sheep. To address these aims, Dr. Pearce proposes a series of mechanistic studies utilizing in vitro vessel contraction techniques, cytosolic calcium studies, sarcoplasmic reticulum calcium mass determinations, IP3-receptor radioligand binding studies, G-protein activation and inhibition protocols, PKC inhibition studies, and MLC phosphorylation assays. To evaluate the influence of differences in arterial size and type, all of these experiments will be conducted in segments obtained from both common carotid and middle cerebral arteries.
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