Effects of riluzole and flufenamic acid on eupnea and gasping of neonatal mice in vivo.
The pre-Bötzinger complex (PBC), part of the ventral respiratory group that is responsible for inspiratory rhythm generation, contains at least two types of pacemaker neurons. In vitro studies have shown that bursting properties of one type of pacemaker relies on a riluzole-sensitive persistent sodium current, whereas bursting of a second type is sensitive to flufenamic acid (FFA), a calcium-dependent nonspecific cationic current blocker. In vitro, under control conditions, the PBC generates fictive eupneic activity that depends on both riluzole-sensitive and FFA-sensitive pacemaker neurons. During hypoxia the PBC generates fictive gasping activity and only riluzole-sensitive pacemaker neurons appear to be necessary for this rhythm. We carried out pharmacological experiments to test the role of respiratory pacemaker neurons in vivo by performing plethysmographic recordings on neonate mice. As reported in vitro, eupnea activity in vivo is abolished only if both FFA and riluzole are coadministered intracisternally, but not when either of them is administered independently. On the other hand riluzole, but not FFA, drastically reduced gasping generation and compromised the ability of mice to autoresucitate. Neither substance P nor forskolin was able to reestablish respiratory activity after riluzole and FFA coapplication. Our results confirm in vitro reports and suggest that eupnea generation in neonates requires a complex neuronal network that includes riluzole- and FFA-sensitive elements and that gasping activity depends mostly on a riluzole-sensitive mechanism.
Peña
Fernando
F
Departamento de Farmacobiología, Cinvestav-Sede Sur, Calz. de los Tenorios 235, Col. Granjas Coapa, 14330 México, D.F., Mexico. jfpena@cinvestav.mx
Aguileta
Miguel-Angel
MA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005439:Flufenamic Acid / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D007276:Injections, Intraventricular; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009415:Nerve Net / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D012125:Respiratory Center / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects*; D019782:Riluzole / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D018691:Excitatory Amino Acid Antagonists; D007473:Ion Channels; D018698:Glutamic Acid; D005439:Flufenamic Acid; D019782:Riluzole