Aoki Cynthia R A, Liu Hattie, Downey Gregory P, Mitchell Jane, Horner Richard L
Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Am J Respir Crit Care Med. 2006 Mar 1;173(5):555-65. doi: 10.1164/rccm.200509-1469OC. Epub 2005 Dec 1.
Previous studies modulating pharyngeal muscle activity with pharmacologic approaches have targeted membrane receptors on pharyngeal motoneurons. Whether modulation of intracellular pathways can increase pharyngeal muscle activity, however, has not been investigated but is relevant to pharmacologic treatments of obstructive sleep apnea.
To determine if modulating the second messenger cyclic adenosine-3'-5'-monophosphate (cAMP) at the hypoglossal motor nucleus (HMN) will increase genioglossus activity across sleep- wake states.
Forty-eight rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states and genioglossus and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN to perfuse artificial cerebrospinal fluid and (1) forskolin (500 microM, adenylyl cyclase activator to increase cAMP), (2) a cAMP analog (500 microM), (3) iso-butyl-methylxanthine (IBMX; 300 microM, phosphodiesterase inhibitor), or (4) a cyclic guanosine-3'-5'-monophosphate (cGMP) analog (500 microM, 8-Br-cGMP).
Forskolin and the cAMP analog at the HMN increased respiratory-related and tonic genioglossus activities in wakefulness and non-REM sleep but not REM sleep. IBMX did not affect genioglossus activity in awake or sleeping rats. However, IBMX abolished the robust excitatory responses to serotonin and phenylephrine at the HMN, but responses to non-N-methyl-D-aspartate receptor activation remained. These effects of IBMX were mimicked by 8-Br-cGMP.
Genioglossus responses to manipulation of cAMP at the HMN are differentially modulated by sleep-wake state. Selective abolition of serotonin and phenylephrine responses after IBMX suggests that under conditions of nonspecific phosphodiesterase inhibition the HMN is unresponsive to certain, otherwise potent, excitatory inputs. Similar responses with 8-Br-cGMP suggest this effect is likely mediated by cGMP pathways.
以往采用药理学方法调节咽肌活动的研究，其靶点是咽运动神经元上的膜受体。然而，细胞内信号通路的调节是否能增强咽肌活动尚未得到研究，但这与阻塞性睡眠呼吸暂停的药物治疗相关。
确定在舌下运动核（HMN）调节第二信使环磷酸腺苷（cAMP）是否会在睡眠-觉醒状态下增强颏舌肌活动。
48只大鼠植入脑电图和颈部电极以记录睡眠-觉醒状态，并植入颏舌肌和膈肌电极以记录呼吸肌活动。将微透析探针插入HMN，灌注人工脑脊液，并分别注入（1）福斯可林（500微摩尔，腺苷酸环化酶激活剂以增加cAMP）、（2）一种cAMP类似物（500微摩尔）、（3）异丁基甲基黄嘌呤（IBMX；300微摩尔，磷酸二酯酶抑制剂）或（4）一种环磷酸鸟苷（cGMP）类似物（500微摩尔，8-溴-cGMP）。
HMN处的福斯可林和cAMP类似物在清醒和非快速眼动睡眠中增加了与呼吸相关的和紧张性颏舌肌活动，但在快速眼动睡眠中未增加。IBMX对清醒或睡眠大鼠的颏舌肌活动没有影响。然而，IBMX消除了HMN对5-羟色胺和去氧肾上腺素的强烈兴奋反应，但对非N-甲基-D-天冬氨酸受体激活的反应仍然存在。8-溴-cGMP模拟了IBMX的这些作用。
颏舌肌对HMN处cAMP操纵的反应在睡眠-觉醒状态下受到不同调节。IBMX后5-羟色胺和去氧肾上腺素反应的选择性消除表明，在非特异性磷酸二酯酶抑制的情况下，HMN对某些原本有效的兴奋性输入无反应。8-溴-cGMP的类似反应表明这种作用可能由cGMP信号通路介导。
