title: Prostaglandin E2 differentially modulates the central control of eupnoea, sighs and gasping in mice.
abstract: Prostaglandin E2 (PGE2) augments distinct inspiratory motor patterns, generated within the preBötzinger complex (preBötC), in a dose-dependent way. The frequency of sighs and gasping are stimulated at low concentrations, while the frequency of eupnoea increases only at high concentrations. We used in vivo microinjections into the preBötC and in vitro isolated brainstem slice preparations to investigate the dose-dependent effects of PGE2 on the preBötC activity. Synaptic measurements in whole cell voltage clamp recordings of inspiratory neurons revealed no changes in inhibitory or excitatory synaptic transmission in response to PGE2 exposure. In current clamp recordings obtained from inspiratory neurons of the preBötC, we found an increase in the frequency and amplitude of bursting activity in neurons with intrinsic bursting properties after exposure to PGE2. Riluzole, a blocker of the persistent sodium current, abolished the effect of PGE2 on sigh activity, while flufenamic acid, a blocker of the calcium-activated non-selective cation conductance, abolished the effect on eupnoeic activity caused by PGE2. Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E2 (PGE2) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBötzinger complex (preBötC), a medullary area that is critical for breathing. Low concentrations of PGE2 (100-300 nm) increased the sigh frequency, while higher concentrations (1-2 μm) were required to increase the eupnoeic frequency. The concentration-dependent effects were similarly observed in the isolated preBötC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current (INap), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium-activated non-selective cation conductance (ICAN ) abolished the effect of PGE2 on fictive eupnoea at higher concentrations. At the cellular level PGE2 significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE2 affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE2 differentially modulates sigh, gasping and eupnoeic activity by differentially increasing INap and ICAN currents in preBötC neurons.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, 98101, USA; Department of Neurological Surgery, University of Washington, Seattle, WA, 98104, USA; Department of Neurology, University of Tübingen, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Henner
authors.initials: H
authors.lastname: Koch
authors.forename: Cali
authors.initials: C
authors.lastname: Caughie
authors.forename: Frank P
authors.initials: FP
authors.lastname: Elsen
authors.forename: Atsushi
authors.initials: A
authors.lastname: Doi
authors.forename: Alfredo J
authors.initials: AJ
authors.lastname: Garcia
authors.forename: Sebastien
authors.initials: S
authors.lastname: Zanella
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology*; D002104:Cadmium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology*; D005260:Female; D005439:Flufenamic Acid / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012119:Respiration / Q000187:drug effects; D019782:Riluzole / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D026941:Sodium Channel Blockers; D002104:Cadmium; D005439:Flufenamic Acid; D019782:Riluzole; D015232:Dinoprostone