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

Abstract

Anesthetics are widely used for animal research on respiratory control in vivo, but their effect on breathing and CO 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 O consumption. Neither ketamine nor urethane decreased chemosensitivity of 5-HT neurons. These results indicate that baseline breathing and/or CO 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. 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.

Arterial blood sampling in male CD-1 and C57BL/6J mice with 1% isoflurane is similar to awake mice

“…The pattern of breathing was quantified in C57BL/6J mice exposed to air, hypoxic gas, and hypercapnic gas. These experiments were performed to confirm previous reports that NO ISO and 1% ISO responses are not different when breathing room air, but 1% ISO does blunt the ability to respond to hypercapnia compared with NO ISO (27, 28). The addition of hypoxic gas allowed for characterizing another respiratory challenge with NO ISO and 1% ISO.…”

Neurotransmitter networks in mouse prefrontal cortex are reconfigured by isoflurane anesthesia

“…An additional complexity is that although measured changes in neurotransmitter concentrations were likely caused by isoflurane-induced neuronal hyperpolarization (Ries and Puil 1999), changes in breathing are known to produce significant changes in human prefrontal cortical function (Heck et al 2019;Thomas et al 2005). None of the anesthetized mice in the present study exhibited significant bradypnea, but subanesthetic concentrations of isoflurane can decrease the hypercapnic ventilatory response in B6 mice (Massey and Richerson 2017). Core body temperature was maintained in the anesthetized mice, yet isoflurane can cause a decrease in brain temperature (Shirey et al 2015).…”

Alleviation of methyl isocyanate−induced airway obstruction and mortality by tissue plasminogen activator

“…A second issue impacting the efficacy of therapy in this model is that accessing the airway of the rat to allow intratracheal drug administration requires repeated isoflurane anesthesia. Acutely, this decreases ventilatory drive 45–47 and thereby can accelerate or worsen respiratory failure, sometimes critically. It is, therefore, possible that higher levels of survival in this model were limited by the additional respiratory depressive effect of repeated isoflurane in the already severely compromised MIC‐exposed animals.…”