Department of Physiology, University of Toronto, Toronto, Canada.
Department of Medicine, University of Toronto, 3206 Medical Sciences Building, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Sci Rep. 2022 Sep 1;12(1):14896. doi: 10.1038/s41598-022-19233-1.
Successful cholinergic-noradrenergic pharmacotherapy for obstructive sleep apnea (OSA) is thought to be due to effects at the hypoglossal motor nucleus (HMN). Clinical efficacy varies with muscarinic-receptor (MR) subtype affinities. We hypothesized that oxybutynin (cholinergic agent in successful OSA pharmacotherapy) is an effective MR antagonist at the HMN and characterized its efficacy with other antagonists. We recorded tongue muscle activity of isoflurane anesthetized rats (121 males and 60 females, 7-13 per group across 13 protocols) in response to HMN microperfusion with MR antagonists with and without: (i) eserine-induced increased endogenous acetylcholine at the HMN and (ii) muscarine. Eserine-induced increased acetylcholine decreased tongue motor activity (p < 0.001) with lesser cholinergic suppression in females versus males (p = 0.017). Motor suppression was significantly attenuated by the MR antagonists atropine, oxybutynin, and omadacycline (MR2 antagonist), each p < 0.001, with similar residual activity between agents (p ≥ 0.089) suggesting similar efficacy at the HMN. Sex differences remained with atropine and oxybutynin (p < 0.001 to 0.05) but not omadacycline (p = 0.722). Muscarine at the HMN also decreased motor activity (p < 0.001) but this was not sex-specific (p = 0.849). These findings have translational relevance to antimuscarinic agents in OSA pharmacotherapy and understanding potential sex differences in HMN suppression with increased endogenous acetylcholine related to sparing nicotinic excitation.
成功的胆碱能-去甲肾上腺素药理学治疗阻塞性睡眠呼吸暂停（OSA）被认为是由于舌下运动核（HMN）的作用。临床疗效因毒蕈碱受体（MR）亚型亲和力而异。我们假设奥昔布宁（成功治疗 OSA 药理学中的胆碱能药物）是 HMN 中有效的 MR 拮抗剂，并对其与其他拮抗剂的疗效进行了表征。我们记录了异氟烷麻醉大鼠的舌肌活动（121 只雄性和 60 只雌性，每组 7-13 只，跨越 13 个方案），以响应 HMN 内 MR 拮抗剂的微灌注，包括：（i）在 HMN 内增加内源性乙酰胆碱的毒蕈碱和（ii）蕈碱。毒蕈碱诱导的乙酰胆碱增加减少了舌运动活动（p<0.001），而女性的胆碱能抑制作用小于男性（p=0.017）。MR 拮抗剂阿托品、奥昔布宁和奥马达西环素（MR2 拮抗剂）显著减轻了运动抑制，p 值均<0.001，各药物之间的残余活性相似（p 值≥0.089），表明在 HMN 中具有相似的疗效。阿托品和奥昔布宁（p<0.001 至 0.05）的性别差异仍然存在，但奥马达西环素（p=0.722）没有差异。HMN 中的蕈碱也降低了运动活动（p<0.001），但这与性别无关（p=0.849）。这些发现对 OSA 药理学治疗中的抗毒蕈碱药物以及理解与尼古丁兴奋有关的内源性乙酰胆碱增加导致的 HMN 抑制中的潜在性别差异具有转化意义。
