Abstract Obstructive sleep apnea syndrome (OSAS) is a disorder in which apnea and hypopnea occur during sleep due to upper airway obstruction. Although the current gold standard treatment, Continuous positive airway pressure (CPAP) therapy, has been shown to be effective, the adherence of this treatment is low. And there is a need to create oral drugs with high therapeutic effects. P2X3 receptor is a ligand-gated calcium channel and known to function by forming a homomer consisting only of P2X3 subunit (P2X3 homomer) or a heteromer containing P2X2 subunit (P2X2/3 heteromer). These receptors are expressed in the carotid body responsible for hypoxia sensing in peripheral blood and hypoxic ventilatory response (HVR). HVR and hypercapnic ventilatory response (HCVR) are known to reflect respiratory instability which is thought to be one of the mechanisms inducing apnea in patients with OSAS. In non-clinical studies, P2X3 antagonists have been reported to suppress HVR and are expected to treat respiratory instability in patients with OSAS. However, these studies have used drugs with low selectivity for P2X3 homomer and P2X2/3 heteromer, and it is not clear which receptor contributes significantly to this effect. In this study, we examined the effect of sivopixant, P2X3 antagonist created in-house, on HVR and HCVR using whole body plethysmography. In addition, we used compound with higher selectivity for P2X3 homomer than sivopixant (Compound A) to identify receptors that contribute to HVR and HCVR. As a result, sivopixant significantly suppressed HVR and slightly suppressed HCVR in healthy rats. On the other hand, Compound A did not suppress HVR even at a dose that inhibited P2X3 homomer to the same extent as sivopixant. Therefore, it was suggested that the suppression of HVR in healthy rats was due to inhibition of P2X2/3 heteromer rather than P2X3 homomer. Since these results were obtained using healthy rats, however it has been reported that in specific pathological models exhibiting an unstable breathing phenotype, the expression of the P2X3 subunit is increased. Therefore, further studies are needed to verify the contribution of P2X3 homomer and P2X2/3 heteromer in pathological condition. This abstract is funded by: Shionogi & Co., Ltd.
Kimpara et al. (Fri,) studied this question.