The effects of ondansetron on sleep-disordered breathing in the English bulldog

Abstract

Serotonin and serotoninergic drugs have significant effects on respiration, at many sites throughout the nervous system, and serotonin has been implicated in the pathogenesis of obstructive sleep apnea. Thus, understanding the serotoninergic mechanisms underlying respiratory control may help discover novel pharmacotherapies for sleep-disordered breathing. Ondansetron, a serotonin (5-HT) antagonist selective for the 5-HT3 receptor subtype has recently been shown to suppress sleep-related central apneas in rats, particularly in rapid-eye-movement (REM) sleep. To evaluate the potential of ondansetron in the treatment of obstructive sleep-disordered breathing, we have performed randomized trials of two doses of ondansetron (20 and 40 mg orally) and placebo (4 studies for each of the 3 conditions) in our animal model of obstructive sleep apnea, the English Bulldog. Ondansetron significantly reduced the respiratory disturbance index (RDI) in REM sleep from 24.15+/-4.85 events/hour at placebo to 11.01+/-1.56 events/hour with high dose treatment, n=4, p<0.05. In contrast, the effects of drug on the RDI in non-rapid-eye-movement (NREM) sleep (5.23+/-1.30 events/hour, placebo; 4.31+/-1.36, with 20 mg ondansetron and 2.89+/-1.30 with 40 mg ondansetron, n=4) were not significant. Ondansetron, however, had no effect on either sleep efficiency or sleep architecture, and there were no effects on either oxyhemoglobin saturation nadirs or on the sleep time with saturations <90%. Although a trend towards reduction in the latter measure of oxygenation was seen at the higher dose of ondansetron. These data suggest a therapeutic potential for ondansetron in obstructive sleep-disordered breathing, particularly REM sleep apnea.