title: Maintenance of gasping and restoration of eupnea after hypoxia is impaired following blockers of alpha1-adrenergic receptors and serotonin 5-HT2 receptors.
abstract: In severe hypoxia or ischemia, normal eupneic breathing fails and is replaced by gasping. Gasping serves as part of a process of autoresuscitation by which eupnea is reestablished. Medullary neurons, having a burster, pacemaker discharge, underlie gasping. Conductance through persistent sodium channels is essential for the burster discharge. This conductance is modulated by norepinephrine, acting on alpha 1-adrenergic receptors, and serotonin, acting on 5-HT2 receptors. We hypothesized that blockers of 5-HT2 receptors and alpha 1-adrenergic receptors would alter autoresuscitation. The in situ perfused preparation of the juvenile rat was used. Integrated phrenic discharge was switched from an incrementing pattern, akin to eupnea, to the decrementing pattern comparable to gasping in hypoxic hypercapnia. With a restoration of hyperoxic normocapnia, rhythmic, incrementing phrenic discharge returned within 10 s in most preparations. Following addition of blockers of alpha 1-adrenergic receptors (WB-4101, 0.0625-0.500 microM) and/or blockers of 5-HT2 (ketanserin, 1.25-10 microM) or multiple 5-HT receptors (methysergide, 3.0-10 microM) to the perfusate, incrementing phrenic discharge continued. Fictive gasping was still induced, although it ceased after significantly fewer decrementing bursts than in preparations than received no blockers. Moreover, the time for recovery of rhythmic activity was significantly prolonged. This prolongation was in excess of 100 s in all preparations that received both WB-4101 (above 0.125 microM) and methysergide (above 2.5 microM). We conclude that activation of adrenergic and 5-HT2 receptors is important to sustain gasping and to restore rhythmic respiratory activity after hypoxia-induced depression.
authors.affiliation: Dept. of Physiology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. walter.m.stjohn@dartmouth.edu
authors.forename: Walter M
authors.initials: WM
authors.lastname: St-John
authors.forename: J C
authors.initials: JC
authors.lastname: Leiter
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D003655:Decerebrate State; D003964:Diaphragm / Q000294:innervation*; D004146:Dioxanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D007650:Ketanserin / Q000494:pharmacology; D008729:Methoxamine / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D010507:Periodicity; D010791:Phrenic Nerve / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D015656:Respiratory Mechanics / Q000187:drug effects*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000662:Amphetamines; D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D007650:Ketanserin; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D008729:Methoxamine; D008784:Methysergide