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

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 sub-anesthetic 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 sub-therapeutic doses. These effects of anesthetics on breathing may alter the interpretation of studies of respiratory physiology in vivo.

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