Eszopiclone and Dexmedetomidine Depress Ventilation in Obese Rats with Features of Metabolic Syndrome

Study Objectives: 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. Design: This study used a within-groups/between-groups experimental design. Setting: University of Michigan. Participants: Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome. Interventions: 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. Measurements and 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 (V-T/T-I) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (T-I/T-TOT) 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.