Serotonin agonists and antagonists in obstructive sleep apnea: therapeutic potential.

Sigrid C Veasey
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引用次数: 119

Abstract

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder associated with substantial cardiovascular and neurobehavioral morbidity. Yet this is a disorder for which there are no widely effective pharmacotherapies. The pathophysiology of obstructive sleep apnea namely, normal respiration in waking with disordered breathing only in sleep, suggests that this disorder should be readily amenable to drug therapy. Over the past 10 years, we have gained tremendous insight into the neurochemical mechanisms involved in state-dependent control of respiration. It is apparent from this work that there are many potential avenues for pharmacotherapies, including several seemingly conflicting directions for serotonergic therapies. Serotonin delivery is reduced to upper airway dilator motor neurons in sleep, and this contributes, at least in part, to sleep-related reductions in dilator muscle activity and upper airway obstruction. The dilator motor neuron post-synaptic serotonin receptors are 5-HT(2A) and 5-HT(2C) subtypes, and in adults the presynaptic 5-HT receptor in motor nuclei is 5-HT(1B), an inhibitory receptor. Serotonin receptors are also found within central respiratory neuronal groups, and these receptor subtypes include 5-HT(1A) (inhibitory) and 5-HT(2) receptors. Peripherally, stimulation of 5-HT(2A), 5-HT(2C) and 5-HT(3) receptor subtypes have an inhibitory effect on respiration via action at the nodose ganglion. Many of these receptor subtypes and their signal transduction pathways may be affected by oxidative stress in obstructive sleep apnea. These alterations will make finding drug therapies for sleep apnea more challenging, but not insurmountable. Future directions are suggested for elucidating safe, well-tolerated serotonergic drugs for this disorder. Tryptophan was one of the first serotonergic drugs tested for OSAHS. This drug was withdrawn from the market as a result of reports linking tryptophan use with eosinophilic myalgia syndrome and life-threatening pulmonary hypertension. Newer drugs with serotonergic activity tested in persons with sleep-disordered breathing include buspirone, fluoxetine and paroxetine. Trials are presently being conducted to evaluate the effects of 5-HT(2A) and 5-HT(3) antagonists on OSAHS. Many of the drugs tested have not shown significant improvement in sleep apnea. However, with continued effort to elucidate the pharmacology of neurochemical control of state-dependent changes in respiratory control, the availability of pharmacological therapy for this disorder is not too far away.

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5 -羟色胺激动剂和拮抗剂在阻塞性睡眠呼吸暂停:治疗潜力。
阻塞性睡眠呼吸暂停低通气综合征(OSAHS)是一种与大量心血管和神经行为发病率相关的普遍疾病。然而,对于这种疾病,目前还没有广泛有效的药物治疗方法。阻塞性睡眠呼吸暂停的病理生理学,即清醒时呼吸正常,只有在睡眠时呼吸紊乱,表明这种疾病应该很容易接受药物治疗。在过去的10年里,我们对呼吸状态依赖控制的神经化学机制有了深刻的了解。从这项工作中可以明显看出,药物治疗有许多潜在的途径,包括一些看似相互矛盾的血清素能治疗方向。5 -羟色胺在睡眠中被减少到上呼吸道扩张运动神经元,这至少在一定程度上有助于与睡眠相关的扩张肌活动减少和上呼吸道阻塞。扩张运动神经元突触后5-羟色胺受体分为5-HT(2A)和5-HT(2C)亚型,成人运动核突触前5-羟色胺受体为5-HT(1B),一种抑制性受体。5-羟色胺受体也存在于中枢呼吸神经元群中,这些受体亚型包括5-HT(1A)(抑制性)和5-HT(2)受体。在外周,5-HT(2A)、5-HT(2C)和5-HT(3)受体亚型的刺激通过作用于结节神经节对呼吸有抑制作用。许多这些受体亚型及其信号转导途径可能受到氧化应激在阻塞性睡眠呼吸暂停。这些变化将使寻找治疗睡眠呼吸暂停的药物更具挑战性,但并非不可克服。未来的方向建议阐明安全,耐受性良好的血清素能药物治疗这种疾病。色氨酸是治疗OSAHS的首批血清素能药物之一。由于有报道将色氨酸的使用与嗜酸性肌痛综合征和危及生命的肺动脉高压联系起来,该药物已从市场上撤出。在睡眠呼吸障碍患者身上测试的具有血清素活性的新药包括丁螺环酮、氟西汀和帕罗西汀。目前正在进行试验,以评估5-HT(2A)和5-HT(3)拮抗剂对OSAHS的影响。许多经过测试的药物并没有显示出对睡眠呼吸暂停的显著改善。然而,随着不断努力阐明呼吸控制状态依赖性变化的神经化学控制的药理学,这种疾病的药物治疗的可用性并不太遥远。
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