Hypoxia inhibits fetal breathing movements, a central effect which is mediated by adenosine and is abolished by transection of the posterior diencephalon. The proposed studies in fetal sheep have three goals; the first is to localize diencephalic neurons which mediate hypoxic inhibition of breathing. Electrical stimulation and specific focal destruction of cells will map diencephalic neurons which depress fetal breathing. Adenosine A1 receptor antoradiography and microinjections of adenosine receptor agonists and antagonists will determine the distribution of adenosine-sensitive cells which trigger hypoxic inhibition. The second goal is to determine the mechanism by which hypoxia increases brain adenosine concentrations. Microdialysis with inhibitors of ecto-5'- nucleotidase and adenosine kinase will be used to measure changes in central adenosine levels during graded hypoxia. These experiments will establish whether the hypoxia-induced increase in brain extracellular adenosine levels is caused by extra- or intracellular degradation of ATP or by decreased intracellular recycling of adenosine. Thus these studies will help determine whether an O2-limitation of mitochondrial oxidative phosphorylation elicits hypoxic inhibition. Because the incidence of fetal breathing returns to normal during prolonged O2 deficiency (>8h), the third goal of this study is to evaluate mechanisms by which breathing might adapt to prolonged hypoxia. Breathing and changes in brain adenosine concentrations will be assessed during sustained hypoxia, and these studies will help determine whether a fall in central levels of adenosine contributes to breathing adaptation. The extent of adenosine receptor desensitization in the diencephalon will also be assessed in vitro by agonist competition of [3H]antagonist binding to A1 adenosine receptors using autoradiographic techniques. These studies will determine whether a change in A1 receptor coupling to guanine nucleotide-binding proteins contributes to hypoxic adaptation. Hypoxic inhibition of fetal breathing appears to be part of a survival mechanism whereby oxygen that would otherwise be used for breathing is made available to the fetal heart and brain; consequently, hypoxic inhibition and the adaptation that occurs during continued oxygen deficiency have relevance to our understanding of hypoxia-induced fetal brain injury. Understanding the mechanism by which hypoxia depresses fetal breathing may also be relevant to infants prone to sudden death (SIDS), to adults with sleep apnea, and to the general control of respiration.
| Koos, Brian J; Rajaee, Arezoo; Ibe, Basil et al. (2016) Thalamic mediation of hypoxic respiratory depression in lambs. Am J Physiol Regul Integr Comp Physiol 310:R586-95 |
| Koos, Brian J; Rajaee, Arezoo (2014) Fetal breathing movements and changes at birth. Adv Exp Med Biol 814:89-101 |
| Koos, Brian J (2011) Adenosine Aýýýa receptors and Oýýý sensing in development. Am J Physiol Regul Integr Comp Physiol 301:R601-22 |
| Maeda, Takatsugu; Koos, Brian J (2009) Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep. Am J Physiol Regul Integr Comp Physiol 296:R693-701 |
| Yan, X; Koos, B J; Kruger, L et al. (2006) Characterization of [125I]ZM 241385 binding to adenosine A2A receptors in the pineal of sheep brain. Brain Res 1096:30-9 |
| Koos, Brian J; Kawasaki, Yoshikazu; Kim, Young-Han et al. (2005) Adenosine A2A-receptor blockade abolishes the roll-off respiratory response to hypoxia in awake lambs. Am J Physiol Regul Integr Comp Physiol 288:R1185-94 |
| Shi, Lijun; Yao, Jiaming; Koos, Brian J et al. (2004) Induced fetal depressor or pressor responses associated with c-fos by intravenous or intracerebroventricular losartan. Brain Res Dev Brain Res 153:53-60 |
| Koos, Brian J; Kawasaki, Yoshikazu; Hari, Ashwinii et al. (2004) Electrical stimulation of the posteromedial thalamus modulates breathing in unanesthetized fetal sheep. J Appl Physiol 96:115-23 |
| Koos, Brian J; Maeda, Takatsugu; Jan, Calvin et al. (2002) Adenosine A(2A) receptors mediate hypoxic inhibition of fetal breathing in sheep. Am J Obstet Gynecol 186:663-8 |
| Koos, B J; Maeda, T (2001) Adenosine A(2A) receptors mediate cardiovascular responses to hypoxia in fetal sheep. Am J Physiol Heart Circ Physiol 280:H83-9 |
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