Hypoxia virtually abolishes breathing movements in normal fetal sheep. Breathing persists with increased depth, however, in fetal lambs with suprapontine brain stem transection. This suggests that hypoxia inhibits breathing by activating oxygen sensitive inhibitory neurons above the pons. The long-term objective of this study is to determine the mechanism by which hypoxia is sensed by the brain. More specifically, the first goal is to separate peripheral and central effects of hypoxia. This will be done by carrying out hypoxia experiments in fetuses with aortic and carotid body denervation. It is hypothesized that breathing in these fetuses will still be depressed, i.e., that hypoxic effects are central. The second goal will be to determine the importance of blood flow limitation at the site where oxygen is sensed. Oxygen content of blood supplying the fetal brain will be lowered by carboxyhemoglobinemia, methemoglobinemia, and anemia. The effects on fetal breathing will be recorded. It is postulated that reducing the O2 content of fetal blood will not abolish breathing activity, suggesting that oxygen supply is blood flow limited. The third goal is to explore a possible mechanism by which hypoxia may alter brain function and respiratory control. It is hypothesized that hypoxia decreases adenosine triphosphate production. Therefore, oligomycin, a selective inhibitor of oxidative phosphorylation, will be administered centrally by carotid artery injection and the effect on breathing activity recorded. If breathing is suppressed similar to hypoxia, intracellular ATP may be critically involved in activating neurons which inhibit breathing. Understanding the mechanism by which hypoxia suppresses breathing may be relevant to depression of respiratory drive as occurs after birth in infants prone to sudden death syndrome and to sleep apnea of chronic obstructive pulmonary disease.
| 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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