Moderate acute intermittent hypoxia (mAIH; 35-55 mmHg PaO₂) elicits phrenic long-term facilitation (pLTF) by a mechanism that requires activation of G_q protein-coupled serotonin type 2 receptors, MEK/ERK MAP kinase and NADPH oxidase activity, and is constrained by cAMP-PKA signaling. In contrast, severe AIH (sAIH; 25-35 mmHg PaO₂) elicits G_s protein-coupled adenosine type 2A receptor-dependent pLTF. Another G_s protein coupled receptor, serotonin 7 receptors, elicits phrenic motor facilitation (pMF) by a mechanism that requires exchange protein activated by cyclic AMP (EPAC) and PI3K/Akt activation, and is constrained by NADPH oxidase activity. Here, we tested the hypothesis that the same downstream signaling mechanisms giving rise to serotonin 7 (vs serotonin 2) receptor-induced pMF underlie sAIH-induced pLTF. In anesthetized rats, sAIH-induced pLTF was compared after pre-treatment with intrathecal (C4) injections of inhibitors for: 1) EPAC (ESI-05); 2) MEK/ERK (UO126); 3) PKA; (KT-5720); 4) PI3K/Akt (PI828); and 5) NADPH oxidase (apocynin). In partial agreement with our hypothesis, sAIH-induced pLTF was abolished by ESI-05 and PI828 and marginally enhanced by apocynin but, surprisingly, was abolished by UO126 and attenuated by KT-5720. Mechanisms of sAIH-induced pLTF reflect elements of both Gq and Gs pathways to pMF, likely as a consequence of the complex, cross-talk interactions between them.

中文翻译：

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严重急性间歇性缺氧诱发膈长期易化的机制

中度急性间歇性缺氧 (mAIH; 35-55 mmHg PaO _{2 ) 通过需要激活 G q}蛋白偶联血清素 2 型受体、MEK/ERK MAP 激酶和 NADPH 氧化酶活性的机制引起膈长期促进 (pLTF) ，并且受cAMP-PKA信号的限制。相反，严重的 AIH (sAIH；25-35 mmHg PaO ₂ ) 会引发 G _s蛋白偶联腺苷 2A 型受体依赖性 pLTF。_另一个G蛋白偶联受体血清素 7 受体通过需要由环 AMP (EPAC) 激活的交换蛋白和 PI3K/Akt 激活的机制引发膈运动促进 (pMF)，并受 NADPH 氧化酶活性的限制。在这里，我们检验了以下假设，即产生 5-羟色胺 7（与 5-羟色胺 2）受体诱导的 pMF 的相同下游信号机制是 sAIH 诱导的 pLTF 的基础。在麻醉大鼠中，在鞘内 (C4) 注射以下抑制剂预处理后比较 sAIH 诱导的 pLTF：1) EPAC (ESI-05)；2) MEK/ERK (UO126)；3）PKA；(KT-5720)；4) PI3K/Akt (PI828)；5) NADPH氧化酶（夹竹桃素）。与我们的假设部分一致，sAIH 诱导的 pLTF 被 ESI-05 和 PI828 消除，并被夹竹桃苷略微增强，但令人惊讶的是，被 UO126 消除并被 KT-5720 减弱。