title: Hyperoxia-induced developmental plasticity of the hypoxic ventilatory response in neonatal rats: contributions of glutamate-dependent and PDGF-dependent mechanisms.
abstract: Rats reared in hyperoxia exhibit a sustained (vs. biphasic) hypoxic ventilatory response (HVR) at an earlier age than untreated, Control rats. Given the similarity between the sustained HVR obtained after chronic exposure to developmental hyperoxia and the mature HVR, it was hypothesized that hyperoxia-induced plasticity and normal maturation share common mechanisms such as enhanced glutamate and nitric oxide signaling and diminished platelet-derived growth factor (PDGF) signaling. Rats reared in 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until 4-5 days of age were studied after intraperitoneal injection of drugs targeting these pathways. Hyperoxia rats receiving saline showed a sustained HVR to 12% O2, but blockade of NMDA glutamate receptors (MK-801) restored the biphasic HVR typical of newborn rats. Blockade of PDGF-β receptors (imatinib) had no effect on the pattern of the HVR in Hyperoxia rats, although it attenuated ventilatory depression during the late phase of the HVR in Control rats. Neither nitric oxide synthase inhibitor used in this study (nNOS inhibitor I and l-NAME) altered the pattern of the HVR in Control or Hyperoxia rats. Drug-induced changes in the biphasic HVR were not correlated with changes in metabolic rate. Collectively, these results suggest that developmental hyperoxia hastens the transition from a biphasic to sustained HVR by upregulating glutamate-dependent mechanisms and downregulating PDGF-dependent mechanisms, similar to the changes underlying normal postnatal maturation of the biphasic HVR.
authors.affiliation: Department of Biology, Bates College, Lewiston, ME 04240, USA. Electronic address: rbavis@bates.edu.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Bavis
authors.affiliation: Department of Biology, Bates College, Lewiston, ME 04240, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: DeAngelis
authors.affiliation: Department of Biology, Bates College, Lewiston, ME 04240, USA.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Horowitz
authors.affiliation: Department of Biology, Bates College, Lewiston, ME 04240, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Reedich
authors.affiliation: Department of Biology, Bates College, Lewiston, ME 04240, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: March
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000627:therapeutic use; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism*; D018496:Hyperoxia / Q000150:complications*; D000860:Hypoxia / Q000209:etiology* / Q000517:prevention & control; D000068877:Imatinib Mesylate; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000068877:Imatinib Mesylate; D019331:NG-Nitroarginine Methyl Ester
keywords: Biphasic hypoxic ventilatory response; Heterokairy; Hypoxic ventilatory depression; NMDA glutamate receptor; Nitric oxide synthase; PDGF-β receptor