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J Appl Physiol 103: 722, 2007; doi:10.1152/japplphysiol.00003.2007c
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POINT-COUNTERPOINT

Rebuttal from St.-John and Paton

Common ground is evident between our proposal and that of Ramirez and Garcia. Ramirez and Garcia state that, for the neurogenesis of eupnea: "There will be conditions when pacemakers are more or are less important". "Is this not close to our concept that, in eupnea, the intrinsic discharge of medullary pacemakers is suppressed and their activities are defined by the pontomedullary neuronal circuit which generates eupnea (3,7)? How does this variable importance of medullary pacemakers" fit with the strong adherence to the medullary "pre-Bötzinger" complex as a noeud vital?

We never denied that the pre-Bötzinger complex is an important component of the pontomedullary respiratory control system. What we denied is that this region contains the exclusive mechanism for the neurogenesis of eupnea. If a noeud vital, why is eupnea only transiently interrupted and/or altered to an ataxic pattern following ablation of neurons in this region (2,6)? Is this alteration, rather than irreversible apnea, now taken as evidence of a noeud vital (1)? It appears inconsistent to consider that this change to an ataxic pattern represents an alteration in the mechanisms of respiratory rhythm generation and yet maintain that all "nongasping" rhythms generated by the isolated medulla must be variants of eupnea (5). As gasping, nongasping medullary rhythms are eliminated, at least sometimes, following a blockade of persistent sodium conductances (4, 5)(9). However, these blockers do not eliminated eupnea of conscious or anaesthetized in vivo or in situ preparations (3, 8). Ramirez and Garcia take exception to our conclusion that pacemakers depending on persistent sodium conductance ("cadmium insensitive") are not essential for the neurogenesis of eupnea by proposing that a blockade of both cadmium-sensitive and cadmium-insensitive pacemakers would be necessary. Yet this hypothesis of dual pacemakers is confounded by the absence of any identification of cadmium-sensitive pacemakers in other than medullary slice preparations. Also, antagonists of cadmium-sensitive pacemakers, such as flufenamic acid, have non-specific blocking actions on synaptic transmission throughout the central nervous system, making interpretation of any changes in eupnea difficult.

As a final word, several investigators (1), including Ramirez and Garcia, evoke plasticity and transformations to deal with the lack of correspondence of their findings from in vitro preparations with those from in situ or in vivo preparations. Perhaps the necessity for so much plasticity and so many transformations to fit aberrant data into the mould of the pre-Bötzinger complex as a noeud vital simply reflects an incorrect mould.

REFERENCES

  1. Feldman JL, Del Negro CA. Looking for inspiration: new perspectives on respiratory rhythm. Nat Rev Neurosci 7: 232–242, 2006.[CrossRef][Web of Science][Medline]
  2. Gray PA, Janczewski WA, Mellen N, McCrimmon DR, Feldman JA. Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons. Nat Neurosci 4: 927–930, 2001.[CrossRef][Web of Science][Medline]
  3. Paton JFR, Abdala APL, Koizumi H, Smith JC, St-John WM. Respiratory rhythm generation during gasping depends on persistent sodium current. Nat Neurosci 9: 311–316, 2006.[CrossRef][Web of Science][Medline]
  4. Pena F, Parkis MA, Tryba AK, Ramirez JM. Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia. Neuron 43: 105–117, 2004.[CrossRef][Web of Science][Medline]
  5. Ramirez JM, Viemari JC. Determinants of inspiratory activity. Respir Physiol Neurobiol 147: 145–157, 2005.[CrossRef][Web of Science][Medline]
  6. St-Jacques R, St-John WM. Transient, reversible apnoea following ablation of the pre-Botzinger complex in rats. J Physiol 520: 303–314, 1999.[Abstract/Free Full Text]
  7. St-John WM. Neurogenesis of patterns of automatic ventilatory activity. Prog Neurobiol 56: 97–117, 1998.[CrossRef][Web of Science][Medline]
  8. St-John WM, Waki H, Dutschmann M, Paton JFR. Maintenance of eupnea of in situ and in vivo rats following riluzole, a blocker of persistent sodium channels. Respir Physiol Neurobiol 155: 97–100, 2006.[CrossRef][Web of Science][Medline]
  9. Tryba AK, Pena F, Ramirez JM. Gasping activity in vitro: a rhythm dependent on 5-HT2A receptors. J Neurosci 26: 2623–2634, 2006.[Abstract/Free Full Text]




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