Isoflurane, ketamine-xylazine, and urethane markedly alter breathing even at subtherapeutic doses

J Neurophysiol. 2017 Oct 1;118(4):2389-2401. doi: 10.1152/jn.00350.2017. Epub 2017 Jul 26.


Anesthetics are widely used for animal research on respiratory control in vivo, but their effect on breathing and CO2 chemoreception has not been well characterized in mice, a species now often used for these studies. We previously demonstrated that 1% isoflurane markedly reduces the hypercapnic ventilatory response (HCVR) in adult mice in vivo and masks serotonin [5-hydroxytryptamine (5-HT)] neuron chemosensitivity in vitro. Here we investigated effects of 0.5% isoflurane on breathing in adult mice and also found a large reduction in the HCVR even at this subanesthetic concentration. We then tested the effects on breathing of ketamine-xylazine and urethane, anesthetics widely used in research on breathing. We found that these agents altered baseline breathing and blunted the HCVR at doses within the range typically used experimentally. At lower doses ventilation was decreased, but mice appropriately matched their ventilation to metabolic demands due to a parallel decrease in O2 consumption. Neither ketamine nor urethane decreased chemosensitivity of 5-HT neurons. These results indicate that baseline breathing and/or CO2 chemoreception in mice are decreased by anesthetics widely viewed as not affecting respiratory control, and even at subtherapeutic doses. These effects of anesthetics on breathing may alter the interpretation of studies of respiratory physiology in vivo.NEW & NOTEWORTHY Anesthetics are frequently used in animal research, but their effects on physiological functions in mice have not been well defined. Here we investigated the effects of commonly used anesthetics on breathing in mice. We found that all tested anesthetics significantly reduced the hypercapnic ventilatory response (HCVR), even at subtherapeutic doses. In addition, ketamine-xylazine and urethane anesthesia altered baseline breathing. These data indicate that breathing and the HCVR in mice are highly sensitive to anesthetic modulation.

Keywords: anesthetic; chemoreceptor; respiration; respiratory control; ventilation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anesthetics, General / administration & dosage
  • Anesthetics, General / pharmacology*
  • Animals
  • Carbon Dioxide / metabolism
  • Carbon Dioxide / pharmacology
  • Cells, Cultured
  • Chemoreceptor Cells / drug effects
  • Chemoreceptor Cells / physiology
  • Dose-Response Relationship, Drug
  • Female
  • Isoflurane / administration & dosage
  • Isoflurane / pharmacology*
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxygen Consumption
  • Respiration / drug effects*
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / physiology
  • Urethane / administration & dosage
  • Urethane / pharmacology*
  • Xylazine / administration & dosage
  • Xylazine / pharmacology*


  • Anesthetics, General
  • Carbon Dioxide
  • Xylazine
  • Urethane
  • Ketamine
  • Isoflurane