Eszopiclone and dexmedetomidine depress ventilation in obese rats with features of metabolic syndrome.
OBJECTIVE
Obesity alters the therapeutic window of sedative/hypnotic drugs and increases the probability of respiratory complications. The current experiments used an established rodent model of obesity to test the hypothesis that the sedative/hypnotic drugs eszopiclone and dexmedetomidine alter ventilation differentially in obese rats compared with lean/fit rats.


METHODS
This study used a within-groups/between-groups experimental design.


METHODS
University of Michigan.


METHODS
Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome.


METHODS
Breathing was measured with whole-body plethysmography after systemic administration of vehicle (control), the nonbenzodiazepine, benzodiazepine site agonist eszopiclone, or the alpha-2 adrenergic receptor agonist dexmedetomidine.


RESULTS
Data were analyzed using two-way analysis of variance and appropriate post hoc comparisons. At baseline, the obese/metabolic syndrome rats had increased respiratory rates (21.6%), lower tidal volumes/body weight (-24.1%), and no differences in minute ventilation compared to lean/fit rats. In the obese rats, respiratory rate was decreased by dexmedetomidine (-29%), but not eszopiclone. In the lean and the obese rats, eszopiclone decreased tidal volume (-12%). Both sedative/hypnotic drugs caused a greater decrease in minute ventilation in the obese (-26.3%) than lean (-18%) rats. Inspiratory flow rate (VT / TI) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (TI / TTOT) in both rat lines was decreased by dexmedetomidine (-16.5%) but not by eszopiclone.


CONCLUSIONS
Dexmedetomidine, in contrast to eszopiclone, decreased minute ventilation in the obese/metabolic syndrome rats by depressing both duty cycle and inspiratory flow rate. The results show for the first time that the obese phenotype differentially modulates the respiratory effects of eszopiclone and dexmedetomidine. These differences in breathing are consistent with previously documented differences in sleep between lean/fit and obese rats. These findings also encourage future studies of obese/metabolic syndrome rats that quantify the effect of sedative/hypnotic drugs on respiratory mechanics as well as hypoxic and hypercapnic ventilatory responses. Continued findings of favorable homology between obese humans and rodents will support the interpretation that these obese rats offer a unique animal model for mechanistic studies.
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
William A
WA
Filbey
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
David T
DT
Sanford
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
Helen A
HA
Baghdoyan
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
Lauren G
LG
Koch
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
Steven L
SL
Britton
Department of Anesthesiology, University of Michigan, Ann Arbor, MI.
Ralph
R
Lydic
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D053961:Azabicyclo Compounds / Q000009:adverse effects / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D020927:Dexmedetomidine / Q000009:adverse effects / Q000494:pharmacology*; D000069582:Eszopiclone; D006935:Hypercapnia / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000503:physiopathology*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D012119:Respiration / Q000187:drug effects*; D015656:Respiratory Mechanics / Q000187:drug effects; D013851:Thinness / Q000378:metabolism; D013990:Tidal Volume
D058647:Adrenergic alpha-2 Receptor Agonists; D053961:Azabicyclo Compounds; D006993:Hypnotics and Sedatives; D010879:Piperazines; D020927:Dexmedetomidine; D000069582:Eszopiclone
alpha-2 adrenergic agonist; benzodiazepine site agonist; metabolic syndrome; non-benzodiazepine; sedatives