Effects of dorsomedial medullary 5-HT2 receptor antagonism on initial ventilatory airway responses to hypercapnic hypoxia in mice

Abstract

The anatomical factors involved in upper airway closure of obstructive sleep apnea (OSA) have been established. However, the mechanisms of repetitive OSA are not well understood. We found that dorsomedial medullary 5-HT2 receptor activity is compensated for by hypercapnia and elicits the immediate onset of poikilocapnic hypoxic ventilatory airway responses. Therefore, the aim of this study was to test the hypothesis that hypercapnia compensates for the immediate onset of poikilocapnic hypoxic ventilatory airway responses induced by dorsomedial medullary 5-HT2 receptors. Adult male mice (C57BL/6N) were intraperitoneally anesthetized with pentobarbital sodium. Microdialysis probes were inserted into the dorsomedial medulla oblongata of the mice. The mice were placed in a double-chamber plethysmograph and were allowed to acclimatize and recover from anesthesia. Mice were then exposed to hypercapnic hypoxic gases (7% O2/5% CO2 in N2) with or without 5-HT2-antagonist (10(-5) M LY-53857) perfusion. Respiratory curves through the head and body chambers were recorded to measure ventilatory airway variables. Extracellular fluid was collected every 5min for HPLC analysis of 5-HT concentration. Hypercapnic hypoxia elicited neither delayed onset of ventilatory augmentation nor immediate airway narrowing with dorsomedial medullary 5-HT2 antagonism. Hypoxic polypnea was shifted downward. The increases in dorsomedial medullary 5-HT release and ventilatory volume were not affected with or without 5-HT2 activity. In conclusion, the onset of poikilocapnic hypoxic ventilatory airway responses mediated via dorsomedial medullary 5-HT2 activity is compensated for by hypercapnia. Maintenance of PCO2 level and CO2 responsiveness, especially with lowered 5-HT2 activity, may be important for preventing repetitive OSA.